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ROS Nad Cancer Good1
ROS Nad Cancer Good1
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*Correspondence: p-schumacker@northwestern.edu
http://dx.doi.org/10.1016/j.ccell.2015.01.007
Reactive oxygen species (ROS) can initiate cancer, but oxidant generation in tumors leaves them vulnerable
to further stresses. In this issue of Cancer Cell, Harris and colleagues show that augmenting oxidant stress in
normal cells limits tumor initiation and progression. Hence, strategic targeting of antioxidant systems may
undermine survival of new tumor cells.
Low levels of reactive oxygen species tate cancer in healthy men taking vitamin zymes that directly scavenge H2O2 or lipid
(ROS) can act as cellular signaling mes- E supplements, suggesting that some hydroperoxides. Harris et al. (2015) em-
sengers by reversibly oxidizing protein oxidant stress may act as a brake on ployed oncogene-induced murine models
thiol groups, thereby modifying protein tumorigenesis. Moreover, in K-ras and B- of mammary cancer (MMTV-PyMT) in
structure and function. Higher levels of raf-driven genetic models of lung cancer, a genetic background lacking GCLM
ROS disrupt cellular processes by non- Sayin et al. (2014) found that NAC and (Gclm / ). Deficiency in GCLM led to a
specifically attacking proteins, lipids, and vitamin E increased tumor cell proliferation 75% decrease in GSH levels, shifting the
DNA. Cellular antioxidant systems help to by attenuating ROS, DNA damage, and cells to a state of chronic oxidant stress.
limit the damage by detoxifying ROS, while p53 expression. These findings suggest The effects on subsequent tumor devel-
other antioxidant systems act by reversing that increases in ROS generation that opment were then assessed.
oxidant-mediated modifications (Figure 1). develop as a cell becomes cancerous Interestingly, increased oxidant stress
Oxidant stress and redox signaling have represent a potentially toxic byproduct of led to fewer tumors that progressed more
been implicated in the genesis of cancer, metabolic reprogramming and antioxidant slowly than those in mice with normal
and ROS can affect the phenotypic defenses—or exogenous antioxidants— GSH. This suggests that increased oxidant
behavior of cancer cells and their respon- may enhance survival/progression by pro- stress was detrimental to the process of
siveness to therapeutic interventions (Sab- tecting the cell against the antiproliferative tumorigenesis and progression toward
harwal and Schumacker, 2014). Oxidative effects of those oxidant stresses. The in- an invasive phenotype. In related experi-
damage to DNA can certainly promote creases in oxidant stress that develop in ments, they used buthionine sulfoxi-
cancer-causing mutations. Oncogenic newly formed tumor cells may render mine (BSO), an inhibitor of GSL, to
transformation of fibroblasts is associated them vulnerable to therapeutic interven- suppress GSH synthesis. When adminis-
with increases in basal levels of oxidative tions that act by further augmenting tered continuously upon weaning, BSO
signaling that may drive proliferation and oxidant generation (Trachootham et al., depleted GSH levels, augmented DNA
promote further mutations. The impor- 2006; Schumacker, 2006). In that sense, oxidation and conferred protection against
tance of ROS in driving cancer progression tumor cells engage in a deadly dance tumorigenesis in a manner that mirrored
was demonstrated by Gao et al. (2007), where some oxidants contribute to muta- the response in the GCLM-deficient mice.
who administered the antioxidant N-acetyl tion and growth while excessive stress Curiously, the effects of BSO on DNA dam-
cysteine (NAC) to mice carrying tumor slows proliferation and threatens survival. age and the protection were lost when
xenografts. They observed a decrease in In this issue of Cancer Cell, Harris et al. BSO was started later, after the appear-
tumor growth that was traced to a redox- (2015) provide important new insight into ance of tumors. They conclude that the
mediated attenuation in levels of the this complex field. Using a combination oxidant stress mediated by GSH depletion
transcription factor, Hypoxia-Inducible of genetic and pharmacological tools inhibited tumorigenesis because, in the
Factor-1 (HIF-1) (Gao et al., 2007). Thus, to disrupt redox homeostasis, they as- setting of oncogene-induced ROS genera-
HIF-1 activation by oxidant signals en- sessed the consequences in terms of tion, it pushed the tumor cells over the cliff
hances the survival and progression tumor initiation and progression. Their as they emerged. They suggest that alter-
of tumors by upregulating genes regu- study focuses on glutathione (GSH), a tri- nate antioxidant mechanisms may have
lating glycolysis, angiogenesis, and cell peptide that plays a key role in antioxidant protected established tumors from this
metabolism. defenses. GSH synthesis requires L- double-hit stress. Of course an alternative
The idea that ROS-driven oxidant stress cysteine, L-glycine, and L-glutamic acid possibility is that BSO did not affect DNA
initiates cancer and drives progression and involves an enzyme complex (gluta- oxidation or progression in the established
has fueled a long-standing interest in the mate cysteine ligase, GSL) consisting of tumors because it was less able to access
use of antioxidants to prevent cancer. catalytic (GCLC) and amplifier (GCLM) the tumor interiors.
Yet a large-scale prospective randomized subunits. While GSH itself can scavenge Interesting insight arises from their
clinical trial detected an increase in pros- ROS, its primary function is to support en- studies of PyMT;Gclm / primary
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