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Diana Barb, Catherine J Williams, Anke K Neuwirth, and Christos S Mantzoros
ABSTRACT Adiponectin, an adipocyte-secreted hormone that plays an important role in diabetes and cardiovascular disease, may also be of importance in the development and progression of several malignancies. Circulating adiponectin concentrations, which are determined mainly by genetic factors, nutrition, and adiposity, are lower in patients with breast, endometrial, prostate, and colon cancer. It has thus been proposed that adiponectin may be a biological link between obesity (especially central obesity) and increased cancer risk. Adiponectin may influence cancer risk through its well-recognized effects on insulin resistance, but it is also plausible that adiponectin acts on tumor cells directly. Several cancer cell types express adiponectin receptors that may mediate the effects of adiponectin on cellular proliferation. Herein, we review recent evidence supporting a role of serum adiponectin concentrations as a novel risk factor and possible diagnostic marker for obesity-related malignancies, including cancers of the breast, endometrium, colon, and prostate. Further studies are needed to fully elucidate the potential role of adiponectin in cancer diagnostics and therapeutics. Am J Clin Nutr 2007; 86(suppl):858S– 66S. KEY WORDS Adiponectin, ACRP30, AMPK, cancer, insulin resistance, obesity
Adipose tissue, which is the largest endocrine organ in the body (1), plays an important role in regulating energy metabolism and inflammation and has also been associated with several cancers. Adiponectin, a 30-kDa complement C1q-related protein, is the most abundant gene product secreted by fat cells (2) and is a key regulator of insulin sensitivity (3, 4) and inflammation (5, 6). Adiponectin modulates several physiologic processes, such as metabolism of glucose and fatty acids (7), and decreased plasma adiponectin concentrations are associated with insulin resistance, type 2 diabetes (8), and atherosclerosis (9). In addition, it was recently shown that adiponectin may play a role in the development and progression of various types of malignancies, as reviewed herein.
The gene for adiponectin is located on human chromosome 3q27 (13), a region identified as a susceptibility locus for the metabolic syndrome and type 2 diabetes in whites (14). Adiponectin is a 244 –amino acid protein that circulates in human plasma as a homopolymer or as full-length adiponectin (fAd or Acrp30) that comprises up to 18 monomeric units. It has an N-terminal region with high structural homology to collagen VIII, X, and complement C1q and a C-terminal globular domain region that resembles the trimeric topology of tumor necrosis factor-␣ (15). Acrp30 is highly abundant in the circulation, with plasma concentrations in healthy humans of Ȃ10 g/mL, and accounts for Ȃ0.01% of total plasma protein. At least 3 distinct and stable isoforms of Acrp30 have been isolated from Escherichia coli or cultured mammalian cells in both mouse (16) and human (17) serum. Although most active adiponectin appears to exist in the form of full-length or high molecular weight (HMW) adiponectin in plasma (12, 18), low molecular weight (LMW) or trimeric complexes are also present in low abundance (17, 19). Proteolytic cleavage of the full-length molecule at amino acid 110 produces globular adiponectin (gAd or gAcrp30) (20), which is thought to have enhanced potency (21). Oligomerization and posttranslational modifications (ie, glycosylation) of adiponectin are apparently critical for binding to its receptors (22) and determining biological activity (16, 23). Thus, different forms of adiponectin (ie, trimeric versus hexameric and HMW, or globular versus full-length) show distinct biological effects through differential activation of downstream signaling pathways (16, 23, 24). Recent evidence suggests that the HMW adiponectin complex may be the active form of the hormone (25, 26), but this remains to be confirmed. HMW adiponectin correlates more strongly with postload glucose concentrations than does total adiponectin (26), and changes in the ratio of HMW to total adiponectin are closely associated with improvements in insulin sensitivity during thiazolidinedione
1 From the Division of Endocrinology, Diabetes and Metabolism and Disease, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. 2 Presented at the 8th Postgraduate Nutrition Symposium “Metabolic Syndrome and the Onset of Cancer,” held in Boston, MA, March 15–16, 2006. 3 Supported by a discretionary grant from Beth Israel Deaconess Medical Center and by a grant-in-aid from Tanita Corporation. 4 Address reprint requests to CS Mantzoros, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Stoneman 816, Boston, MA 02215. E-mail: firstname.lastname@example.org.
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Adiponectin, which is also referred to as gelatin-binding protein-28 (GBP28) (10), AdipoQ (11), ACP30 (Acrp30) (12), or gene product of the adipose most abundant gene transcript-1 (apM1) (2), is secreted predominantly by white adipose tissue.
Am J Clin Nutr 2007;86(suppl):858S– 66S. Printed in USA. © 2007 American Society for Nutrition
Higher adiponectin concentrations are associated with a moderate decrease in risk of coronary artery disease in diabetic men (66) and with improved glycemic control and lipid concentrations and reduced inflammation in diabetic women (67). Thus. trimeric Acrp30 was the most potent isoform in terms of suppression of hepatocyte glucose production and reduction of serum glucose concentrations as compared with the higher order oligomeric forms (28). independently of age. whereas changes in total adiponectin concentrations are not (25). Other studies have suggested that both fAd and gAd stimulate fatty acid oxidation. Reduced expression or down-regulation of adiponectin receptors has been reported in skeletal muscle and adipose tissue in leptin-deficient ob/ob (40) and db/db (41) mice. T-cadherin. 44. Full-length adiponectin. as well as in fa/fa Zucker rats (42). these 7-transmembraneregion proteins have an internal N terminus region and an external C terminus. ADIPONECTIN AND CANCER EPIDEMIOLOGY Downloaded from www. glucose uptake. increase phosphorylation and activation of AMPK in skeletal muscle (23). Both have unique distributions and affinities for the different forms of circulating adiponectin. but not gAd.ADIPONECTIN AND CANCER 859S treatment in humans. we recently showed that closer adherence to a Mediterranean-style dietary pattern is significantly associated with circulating adiponectin concentrations (49). 52) and also limits adipocyte production of HMW adiponectin in vivo and in cultured adipocytes (52). Finally. Also. AdipoR2 is predominantly expressed in the liver and has intermediate affinity for both forms of adiponectin (18. Crosssectionally. 57). 54) and in congenital lipodystrophic syndromes (55) and have a strong inverse association with parameters of central and overall obesity. and estradiol concentrations (56. Chronic caloric restriction leading to weight loss increases adiponectin concentrations (48. was also found to bind strongly to HMW adiponectin. 21). Testosterone administration suppresses serum total adiponectin concentrations in mice and in men (51. down-regulates genes involved in gluconeogenesis through 5'-AMP-activated protein kinase (AMPK) in the liver (27). increase with fasting and decrease with feeding) and pathologic conditions (40). at levels similar to liver for AdipoR2 and even greater than in muscle for AdipoR1 (31). and insulin-like . the expression of AdipoR1/R2 is inversely correlated with plasma insulin concentrations in vivo under physiologic (ie. which suggests that leptin may also play a role in adiponectin receptor regulation. such as C-reactive protein and fibrinogen (1. which suggests that adiponectin could exert direct effects on these cells via signaling through its receptors. as opposed to the usual topology of G proteincoupled receptors (30). but also by breast cancer cells (35–38). but not hexameric and HMW Acrp30. however. Of note.ajcn. further evidence suggests that trimeric Acrp30 and gAcrp30. it is most abundant in skeletal muscle but is also expressed in endothelial cells and other tissues. 59). it is believed that it does not signal internally but may act as a co-receptor (22). adiponectin has also been linked to several inflammatory markers. plasma adiponectin concentrations are more closely related to insulin sensitivity and fasting insulinemia than to adiposity (60). normal (39) and cancerous endometrial cells. 50). and colon and neuroblastoma cancer cell lines (C Mantzoros. and lactate production through AMP activation in C2C12 myocytes (29). but whether these polymorphisms are also associated with risk of malignancies remains to be studied. In addition to the strong and consistent inverse association between adiponectin and insulin resistance (63. above and beyond any effect of specific food items. 2010 Studies conducted by our research group found lower circulating adiponectin concentrations to be associated with an increased risk of breast cancer in postmenopausal women. Higher intakes of fiber and magnesium have been associated with increased plasma adiponectin concentrations in diabetic men (48). Adiponectin concentrations have been inversely associated with glycemic load in a dose-dependent manner (48). with increased expression in adipose tissue and cultured adipocytes but not in cultured myocytes (40. and low adiponectin concentrations at baseline (before and after adjustment for body fat) precede a decrease in insulin sensitivity (61). menopausal status. initial studies indicate that activation of adiponectin receptors by adiponectin limits the proliferation of breast cancer cells in vitro (37). this remains an active area of research. Adiponectin receptors are expressed not only by prostate (32–34) and hepatocellular (32) carcinoma cell lines. Circulating concentrations of adiponectin are reduced in obesity and type 2 diabetes (53. 58. a cellsurface receptor involved in calcium mediated cell-cell interactions and signaling located in endothelial and smooth muscle cells. In one study. leptin. independently of body mass index (BMI). unpublished data. AdipoR1 is expressed ubiquitously. however. Plasma adiponectin concentrations in humans have also been found to be positively correlated with HDL cholesterol and negatively correlated with triacylglycerols and apolipoprotein B-100 (65). Both adiponectin receptors are markedly expressed in pancreatic ␤-cells. 2007). The expression of adiponectin receptors is negatively regulated by insulin through activation of phosphoinositide 3 kinase and inactivation of Foxo1 (40).org by on July 28. Thus. These sex-specific differences in circulated adiponectin concentrations may reflect differences in end organ adiponectin sensitivity or adiponectin production rates. adiponectin receptor expression is also regulated by peroxisome proliferator-activated receptor-␣ and peroxisome proliferator-activated receptor-␥. 65). We recently reported that aging and prolonged exposure to high-fat feeding down-regulate adiponectin concentrations and up-regulate the expression of adiponectin receptors (43). most likely as the result of differences in circulating estrogens or androgens (3. ADIPONECTIN PHYSIOLOGY AND PATHOPHYSIOLOGY Certain polymorphisms of the adiponectin gene promoter have been associated with lower serum adiponectin concentrations in persons with diabetes (46). Dietary factors may also modulate plasma adiponectin concentrations (47). 64). Women have higher adiponectin concentrations than do men independently of fat mass or distribution. Although it has not yet been clarified whether the presence of adiponectin receptors in tumor cells has any functional relevance. and their pathophysiologic significance remains to be determined. AdipoR1 is a high-affinity receptor for gAd with a low affinity for fAd. adiponectin concentrations are associated with hormonal markers of insulin sensitivity (62). Because T-cadherin does not have an intracellular domain. However. 45). several tumor cell lines express AdipoR1 and AdipoR2. Two adiponectin receptor isoforms (AdipoR1 and AdipoR2) have been cloned (30). Structurally. In addition.
after adjustment for central obesity (waist-to-hip ratio). nested case-control study conducted by our group found that plasma adiponectin concentrations were inversely associated with risk of colorectal cancer in men (75). In addition. 38) breast cancer cell lines. in which we found an Ȃ70% reduced risk for men with the highest relative to men with the lowest adiponectin concentrations. leptin. even after adjustment for body size. prospective study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) Study confirmed the relation between lower pre-diagnostic plasma adiponectin concentrations and a higher risk of endometrial cancer in both pre-and postmenopausal women regardless of BMI status (obese versus nonobese) or other obesity-related risk factors. Thus. prospective studies have detected an increased risk of postmenopausal breast (62). BMI. although observational studies cannot prove causation beyond any doubt. endometrial (71. and physical activity (75). 83). Interestingly. depth of invasion. including breast (71. which agrees with the observation that adiponectin treatment suppresses the growth of myelomonocyte cell lines (82). In addition. HMW adiponectin was also found to inhibit dihydrotestosterone. unpublished data. and colorectal (75) cancer with low adiponectin concentrations (Table 1). and other known risk factors of the disease in women under 65 y of age (72). Our research group has also shown that adiponectin is inversely associated with risk of endometrial cancer. in a case-control study. 81). In the same study. the small sample size could have prevented the results from reaching statistical significance. 74). we found that adiponectin concentrations were lower in patients with acute myeloblastic leukemia than in healthy control subjects (81). Adiponectin may act either directly on cancer cells or indirectly by regulating whole-body insulin sensitivity. and that this expression is significantly higher than in nontumorous colorectal tissue from colorectal cancer patients (C Mantzoros. BMI. both prospective observational and interventional studies are warranted to fully elucidate the mechanisms underlying the effects of adiponectin. 85). waist circumference. or hormonal status (74). 70). adiponectin induces apoptosis in myelomonocytic progenitor cells (M1 leukemia lines) in a dose-dependent manner. 81). likely by down-regulating antiapoptotic genes (82). IGF binding proteins. one study reported an inverse correlation (69). evidence from case-control studies indicates that circulating adiponectin concentrations in vivo are inversely associated with the risk of obesity-related malignancies. and other classic risk factors. 84) cancer. This relation is independent of variation in IGF-1. We replicated these results in a larger study (77). women with high BMI and low plasma adiponectin have a risk of endometrial cancer that is 6. but another 2 studies did not confirm these results (62. particularly in a low-estrogen environment. In a small. such as endogenous insulin concentrations. 68). Men with the highest concentrations had an Ȃ60% reduced risk for colorectal cancer compared with those with the lowest concentrations. and tumor stage (79). The elevated expression of AdipoR1 and AdipoR2 further indicate a potential role of adiponectin in the pathogenesis of colorectal cancer. Recent studies have confirmed these findings (73. 86). More recently. Finally. in addition. 2007). prospective case-control study nested within the Nurses’ Health Study and Nurses’ Health Study II cohorts to examine the association between plasma adiponectin concentrations and breast cancer risk (62). case-control. A small case-control study (76) also reported that plasma adiponectin concentrations are significantly lower in subjects with prostate cancer than in patients with benign prostatic hyperplasia or in healthy control subjects. our group (77) and others (76) have shown that plasma adiponectin concentrations are negatively correlated with histologic grade and disease stage. Moreover. a large. This prospective study design provides the time sequence criterion for causality. we have found that colorectal tumors express adiponectin receptors. 72. in addition. Others have confirmed this association regardless of menopausal status (69. Although one prospective study in prostate cancer (78) did not find any association between adipokines (and adiponectin in particular) and prostate cancer.5-fold that in women with normal BMI and higher adiponectin concentrations (71). The lower estrogen concentrations in postmenopausal women may partially explain the lower adiponectin concentrations in these women. it is of note that the technology used to measure adiponectin concentrations was not standard. This finding indicates that altered concentrations of adiponectin may mediate the effect of intraabdominal obesity (80). and T47D (37. retrospective study of patients with histologically confirmed renal cell carcinoma and healthy control subjects matched by sex and age. It remains unclear whether stage or grade of disease is associated with adiponectin concentrations. we found that serum adiponectin concentrations were significantly and inversely associated with renal cell carcinoma after control for BMI. Adiponectin may also play a role in gastric (79) and renal (80) cancer and in leukemia (73. and prostate (76. 78. Plasma adiponectin concentrations have been found to be lower in patients with gastric cancer than in healthy control subjects and to be inversely correlated with tumor size. IGF-2. endometrial (74).860S BARB ET AL growth factor-I (IGF-I) concentrations (37.or IGF-1–stimulated cell growth and to enhance doxorubicin inhibition of prostate cancer cell . In summary. In addition. We also conducted a large. MCF-7 (35. IGF binding protein-3. Other recent studies report that adiponectin can suppress cell growth in the MDAMB-231 (38. however. 70). POTENTIAL MECHANISMS UNDERLYING THE PROTECTIVE ROLE OF ADIPONECTIN IN CARCINOGENESIS Downloaded from www.org by on July 28. case-control. prospective. This finding suggests that adiponectin may play a role in breast cancer etiology.ajcn. This association was independent of age. Another large. the association between adiponectin and renal cell carcinoma became not significant. 2010 Accumulating evidence suggests that adiponectin is an important regulator of cell proliferation. and may also play a role in gastric cancer (79) and leukemia (73. 83). Similar to our previous results in a retrospective study (68). Antiproliferative effects Adiponectin has been shown to drastically suppress the growth of myelomonocyte leukemia cells in vitro (82). only the HMW form of fAd (not LMW fAd or gAd) inhibited the proliferation of androgendependent (LNCaP-FGC) and androgen-independent (DU145 and PC-3) prostate cancer cell lines as well as hepatocellular carcinoma cells (HepG2) (34) at subphysiologic concentrations (1 g/mL). 72. the inverse association between adiponectin concentrations and breast cancer was statistically significant in postmenopausal women only.
ADIPONECTIN AND CANCER 861S TABLE 1 Epidemiologic studies that show an inverse. 0.71.73 (0.89 (0.98) for breast cancer. analysis.89) highest vs lowest quartile of adiponectin 0. the method used is not the standard one because questions about sensitivity of the assay used remain.44 (0. adiponectin The inverse association was independent of other obesity-related risk factors 0.19–0. P 0.10) for breast cancer risk only.29 (0. premenopausal Endometrial cancer Dal Maso et al. 2010 Petridou et al. 2004 (71) Downloaded from www. alcohol.19)2 highest Association present in pre. 2005 (75) Prospective 179/356 American case-control Health Professionals Follow-up Study Retrospective 75/52 Japanese case-control The first prospective study.30 inversely associated with postmenopausal (0. 2005 (79) 0. The association was adiponectin vs controls also strong in nonobese women.56 (0. 2007 (62) 0. 3. Lower adiponectin concentrations in cases and negative association with histologic grade and disease stage. Nonstatistically significant results observed.80–2. Prostate cancer Freedland et al.81)2.87)2 Lower adiponectin concentrations in cases. Gastric cancer Ishikawa et al. Adjusted OR per quintile increase in 0. adiponectin was found to be postmenopausal 1. independent association between adiponectin concentrations and risk of different types of cancers shown as odds ratios (ORs) Cancer and study Breast cancer Mantzoros et al. Lower adiponectin concentrations adiponectin with more advanced stage disease.009 Lower adiponectin concentrations in cases (pre.99) for 1-SD Association found only in postmenopausal increase in adiponectin women. 2007 (74) 0.ajcn. and testosterone. and comments Retrospective 174/167 Greek case-control Retrospective 102/100 Japanese case-control Retrospective 100/100 Taiwanese case-control Retrospective 74/76 Greek case-control Prospective NHS and NHSII case-control 1477/2196 postmenopausal (858/1309) premenopausal (316/506) Retrospective 87/132 Italian case-control Chen et al.63 (1.45 for highest level of BMI and lowest of adiponectin).org by on July 28. 2003 (69) Type of study No.56–0. 2005 (70) Korner et al.95)2 The stage was inversely related to adiponectin concentrations in undifferentiated gastric cancer (n ҃ 32).24–0.46–1.10–0. 2006 (83) Cust et al. 2006 (78) 0. 2007 (77) 0.49–24.97) for all.71–1.57)2 for Confirms the previously published case-control lowest tertile of studies from Europe. Association was independent of age. 2005 (76) Retrospective 30/36 Turkish case-control Prospective 125/125 San case-control Antonio Center for Biomarkers of Risk of Prostate Cancer Retrospective 75/150 Greek case-control Baillargeon et al.and postmenopausal versus lowest tertile of women. HMW adiponectin measurements produced similar results. 0.94) for 1-SD BMI and adiponectin showed multiplicative increase in adiponectin effects on endometrial carcinogenesis (OR ҃ 6.86) top vs First prospective study of adiponectin in bottom quartile of endometrial cancer.90)2 highest vs lowest quintile of adiponectin Colon cancer Wei et al. adiponectin 10.74 (0. 2005 (84) Retrospective 236 cases American case-control Goktas et al. 2004 (68) Miyoshi et al. BMI.94 (0.87–1.5 (4.01)4 P ҃ 0. insulin. (Continued) .42 (0. on adiponectin in relation to colorectal malignancy in men.and postmenopausal women) 0. 0.84–0. 2003 (72) Retrospective 84/84 Greek case-control Retrospective 117/238 American case-control Prospective 284/548 European case-control Soliman et al. 2006 (37) Tworoger et al.3 for 1-SD increase in adiponectin was 0. of cases/controls and population OR (95% CI) or significance Additional results.84 (0.35 (0.14–0.36–0.65) highest vs lowest tertile of adiponectin Michalakis et al.61–8.09 P 0.89 (0. smoking.11) for all The first prospective study of adiponectin in 0.87 (0.48 (0.55–0.25–0.001 Shows association between adiponectin and high-grade disease only in overweight and obese (80 advanced stage/160 organconfined cases).
which facilitates ubiquitination and proteolysis of ␤-catenin by phosphorylation at N-terminal sites (97). unpublished data. 1 Downloaded from www. and comments Serum adiponectin concentrations were inversely associated with renal cancer after controlling for BMI but not after controlling for central obesity (WHR). one is the fact that these studies were performed in a serum-free environment. CLL. In addition. 2007 (80) Type of study BARB ET AL No. Despite the mounting experimental data. activated AMPK positively regulates 2 proteins that are important for the control of growth arrest and apoptosis: p21 and p53 (89). both full-length and globular adiponectin stimulated colonic (HT-29) epithelial cell proliferation (87). cardiomyocytes (92. waist-to-hip ratio. 88). Akt can phosphorylate . but the mechanisms underlying these effects remain unknown.00) P ҃ 0.76 (0. analysis. It also decreases the expression of the transcriptional regulator sterol-regulatoryelement-binding-protein 1c (SREBP-1c).or T-cell origin. mammary tumorigenesis of MDA-MB-231 cells in female nude mice was substantially reduced by either supplementation with recombinant adiponectin or adenovirusmediated overexpression of adiponectin at 7 or 14 d after initial tumor implantation (38). apoptosis was increased by adiponectin treatment. but it was not possible to discriminate whether this decrease was caused by the direct suppressive effects of adiponectin on cell migration and invasion or was secondary to the reduced size of primary tumors in the adiponectin-treated group (38). ALL-B or -T. it is of note that all these in vitro proliferation studies have limitations. cyclin D1 (35). Association was for ALL-B 1.56 (0. and endothelial cells (94. 88). longer treatment with adiponectin (over a period of 2 to 6 h) was also shown to decrease the mRNA expression of the growth regulatory gene c-myc and one of the important G1 regulatory cyclins.34–0. The stabilization and nuclear translocation of ␤-catenin and overexpression of cyclin D1 have been observed in many types of human cancer (96).71–1. myeloproliferative diseases. possibly through modulation of the ␤-catenin–Wnt pathway. It has been hypothesized that the beneficial actions could be explained in part through activation of the AMPK pathway. Although experimental conditions can vary. case-control 161 ALL-B. Retrospective 70/280 Greek case-control Childhood leukemia Petridou et al. P 0. Glycogen synthase kinase-3␤ (GSK-3␤) is one of the enzymes of the ␤-catenin degradation complex.88 (0. Higher adiponectin concentrations in IFN-treated patients.67–1. MPD. In contrast with findings in breast and prostate cancer cell lines. chronic lymphocytic leukemia. the activation of the AMPK pathway was rapid and transient (the effect is maximum in the first 10 min and gone within 30 – 60 min). More recently. Most of the available data support the observation that AMPK may constitute a general intracellular response to adiponectin. which may well differ from the in vivo condition. 38.08 not significant between adiponectin and (0. 2007). 85).001 for MPD Shows lower adiponectin concentrations in CLL and MPD patients than in controls. In some studies (35. AML. AMPK activation suppresses cell proliferation through multiple mechanisms. interferon. which may be sufficient to decrease cell proliferation or inhibit cell growth. adipocytes (90). which inhibits de novo fatty acid synthesis. 86). Also.862S TABLE 1 (Continued) Cancer and study Renal cancer Spyridopoulos et al. NHS. These data clearly support a role of adiponectin in breast carcinogenesis.org by on July 28. the mechanisms underlying the antiproliferative effects of adiponectin are not fully understood. Adiponectin-mediated suppression of cyclin D1 expression and inhibition of cell-cycle progression was observed in MDAMB-231 cells with prolonged treatment (24 h). and we found that adiponectin activates AMPK and one of its major downstream targets acetyl-CoA carboxylase in LNCaP and CWR22Rv1 prostate cell lines (C Mantzoros. This has also been confirmed in MCF-7 breast cancer cells (35). In vivo intratumoral administration of murine adiponectin to mice resulted in significant suppression of T241 fibrosarcoma tumor growth (60% reduction of tumor volumes and weights after weeks of treatment. 3 Analysis in women younger than 65 y. high molecular weight. 95). acute lymphoblastic leukemia of B. pancreatic ␤-cells (91). of cases/controls and population OR (95% CI) or significance 0. 2006 (73) Retrospective 19/19 CLL 30/30 case-control MPD Turkish HMW. 2010 growth (34). A reduction in lung metastasis was also observed in the adiponectin-treated group.94) for AML Inverse correlation between adiponectin 0.10) concentrations and AML.57–1. Nurses’ Health Study. remains inconclusive. because it is activated in response to adiponectin treatment in myocytes and hepatocytes (29).05 Additional results. CLL and MPD Avcu et al. 2006 (81) Retrospective 201/201 (22 AML. IFN.001 for CLL P 0.72) for ALL-T either ALL-B or ALL-T. WHR. Similarly to previous studies. 4 Analysis in overweight and obese subjects. Only 2 studies to date have explored the physiologic relevance of the above data by examining the effects of in vivo adiponectin administration on tumor growth (38. 93). In addition to AMPK activation in MCF-7 cells.ajcn. 2 Controlled for BMI or BMI and other variables. 18 ALL-T) Greek 0. acute myeloblastic leukaemia. including inhibition of enzymes implicated in the regulation of protein (mammalian target of rapamycin) and fatty acids and triacylglycerol synthesis (acetyl-CoA carboxylase and fatty acid synthase). study of the effects of adiponectin on the apoptosis of cancer cells in vitro. but this was not observed in other studies (34.
effects in vitro and in vivo could be by regulating the bioavailability of certain growth factors. Altered concentrations of adiponectin. This affirms that oligomerization may play an essential role in determining the biological activities of adiponectin (100). 100). In addition.org by on July 28. p38 mitogen-activated protein kinase (MAPK). as was recently and thoroughly reviewed elsewhere (98). estradiol (E2) and testosterone (T). It also inhibits the interaction of these factors with their membrane receptors (100).ADIPONECTIN AND CANCER 863S FIGURE 1. Clearly. A summary of the factors that contribute to increased risk of obesity-associated malignancies. PDGF-BB binds to the HMW and MMW forms but not the LMW form of adiponectin. both of which lead to increased conversion of androgens to estrogens (aromatase activity) and increased conversion of “weak” or less biologically active sex hormones to more active hormones. Reduced release or impaired secretion of adiponectin can directly or indirectly through development of insulin resistance or by promoting inflammation (as well decreased sequestration of growth factors not depicted here) contribute toward a higher risk of tumor development. In addition. adiponectin in physiologic concentrations significantly reduces DNA synthesis. including decreased concentrations of adiponectin. A summary of the possible mechanisms reviewed herein is presented in Figure 1. Insulin-sensitizing and antiinflammatory effects Adiponectin’s anticancer properties are also likely explained. Finally. advanced prostate cancer). another potential mechanism by which adiponectin may exert antiproliferative. which suggests that the antiproliferative effect of adiponectin is at least partly due to its selective sequestration of growth factors at a prereceptor level (100). ie. 29). 101). and fibroblast growth factor binds preferably HMW. and peroxisome proliferator-activated receptor-␣ effects (29. in obese individuals there is an increase in the activity of enzymes aromatase and 17-␤-hydroxysteroid dehydrogenase (17␤HSD) in adipose tissue. leading to stabilization and increased concentrations of ␤-catenin (96). because simultaneous down-regulation of both AdipoR1 and AdipoR2 had no effects on adiponectin-mediated inhibition of cell proliferation or ␤-catenin accumulation in MDA-MB-231 cells (38). These findings. there is more to be studied to better understand the mechanisms underlying the antiproliferative effects of adiponectin. ie. insulin. chronic recombinant adiponectin treatment suppressed serum-induced phosphorylation of Akt and GSK-3␤ in MDA-MB-231 cells. Downloaded from www. ie. Moreover. however.ajcn. adiponectininduced phosphorylation and activation of AMPK (27. thus contributing to increased free sex steroid concentrations. Intraperitoneal injection of ACRP30 lowers glucose concentrations in mice (101) and eliminates hyperglycemia in ob/ob. In cultured smooth muscle cells. 2010 and inactivate GSK-3␤. by sequestration of growth factors (see paragraph below) may be one possibility. support the hypothesis that adiponectin modulation of the GSK-3␤/␤-catenin signaling pathway might play a critical role in mediating the inhibitory effects of adiponectin on breast cancer (38). Chronic hyperinsulinemia also causes a decrease in the hepatic synthesis of sex hormone– binding globulin (SHBG). subsequently. adiponectin treatment did not alter ␤-catenin concentrations in T47D cells (38). 30. 102) have been proposed to account for increased insulin sensitivity and fatty acid oxidation in response to adiponectin treatment. ie. action at the prereceptor level. HB-EGF binds all 3 oligomeric complexes of adiponectin (HMW. cyclin D1. by its antiinflammatory and insulin-sensitizing effects (8). this suppressive effect of adiponectin on ␤-catenin in MDA-MB-231 breast cells may be cell type specific. and migration induced by several growth factors (99. and LMW). Although there was no direct evidence in this study of direct alteration of Akt phosphorylation status by adiponectin. Insulin resistance is the product of decreased adiponectin as well as increased concentrations of other adipokines [eg. Another study also showed that adiponectin selectively binds not only platelet-derived growth factor-BB (PDGF-BB). and thus anticarcinogenic. MMW. tumor necrosis factor-␣ (TNF-␣) and interleukin-6 (IL-6)] in obesity. IGF-1 and sex hormones alter cellular proliferation and inhibit apoptosis. at least in part. the intracellular accumulation and nuclear translocation of ␤-catenin and the expression of one of its transcriptional targets. Nevertheless. the fact that adiponectin may modulate the GSK-3␤/␤-catenin pathway could be especially important in cancers that are PTEN deficient and subsequently have constitutive activation of the phosphoinositide 3 kinase–Akt pathway that may contribute to Wnt-1–induced ␤-catenin stabilization (ie. Compensatory hyperinsulinemia can in turn reduce liver synthesis and serum concentrations of insulin-like growth factor binding proteins (IGFBPs) and thus increase concentrations of bioavailable IGF-1 (free IGF-1). was decreased (38). FFA. free fatty acid. but also heparin-binding epidermal growth factorlike growth factor (HB-EGF) and basic fibroblast growth factor. these effects do not seem to be mediated through adiponectin receptors. However. nonobese diabetic and streptozotocin-treated mice (27) by inhibiting both the expression of hepatic gluconeogenic enzymes and the rate of endogenous glucose production (27. . The binding of these growth factors by adiponectin is specific and involves different oligomeric forms and binding sites of adiponectin for each growth factor. cell proliferation. Although the mechanisms underlying the insulin-sensitizing effects of adiponectin are not completely understood.
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