Received: 13 January 2019 | Revised: 3 April 2019 | Accepted: 11 April 2019

DOI: 10.1002/jcp.28740

REVIEW ARTICLE

Autophagy, anoikis, ferroptosis, necroptosis, and endoplasmic

reticulum stress: Potential applications in melanoma therapy

Milad Ashrafizadeh1 | Reza Mohammadinejad2 | Shima Tavakol3 |

Zahra Ahmadi4 | Sahar Roomiani4 | Majid Katebi5

1
Department of Basic Science, Faculty of
Veterinary Medicine, University of Tabriz, Abstract
Tabriz, Iran Melanoma as the most major skin malignancy has attracted much attention, so far.
2
Pharmaceutics Research Center, Institute of
Although a successful therapeutic strategy requires an accurate understanding of the
Neuropharmacology, Kerman University of
Medical Sciences, Kerman, Iran precise mechanisms for the initiation and progression of the melanoma. Several types
3
Cellular and Molecular Research Center, Iran of cell death mechanisms have recently been identified along with conventional cell
University of Medical Sciences, Tehran, Iran
4
death mechanisms such as apoptosis and necrosis. Among those mechanisms,
Department of Basic Science, Faculty of
Veterinary Medicine, Islamic Azad Branch, necroptosis, anoikis, ferroptosis, and autophagy may be considered to have
University of Shushtar, Khuzestan, Iran
remarkable modulatory impacts on melanoma. In the present review, we explain
5
Department of Anatomy, Hormozgan
University of Medical Sciences, Bandar Abbas,
the mechanisms of cell death signaling pathways related to autophagy, ferroptosis,
Hormozgan, Iran anoikis, necroptosis, and reticulum endoplasmic stress in cells and describe how those

Correspondence
mechanisms transduce signals in melanoma cells. Meanwhile, we describe how we can
Milad Ashrafizadeh, Department of basic modulate those mechanisms to eliminate melanoma.
science, Faculty of Veterinary Medicine,
University of Tabriz, Tabriz, Iran.
KEYWORDS
Email: dvm.milad73@yahoo.com
anoikis, autophagy, ferroptosis, melanoma., necroptosis

1 | INTRODUCTION important role of regulated cell death (RCD) in preserving homeostasis

Melanoma, the most common cause of skin malignancy, is resulted from
malignant transformation of melanocytes. It is thought that the
increase of melanoma incidence particularly in western countries is in
part owing to their brighter skin and lower sun protection (Gallagher,
2005). Besides, lack of a sensitive and precise approaches to diagnose
melanoma at the early stages leads to cancer progression and not
properly responding to the therapeutics (Aris & Barrio, 2015; Tarver,
2012). Although there are some promising investigations on the
efficacy of novel nano‐therapeutics on skin repair (Tavakol, Jalili‐
Firoozinezhad, Mashinchian, & Mahmoudi, 2016; Tavakol, Zare,
Hoveizi, Tavakol, & Rezayat, 2019), during recent years, much attention
has been made to kill melanoma cells without affecting healthy cells. By
regards to the importance of cancer therapy and tumor cell mortality,
the precise understanding of the processes involved in cell death is
vital. Research works have manifested a series of pathways which are
involved in the cell homeostasis to eliminate irreversible damaged cells
including cells with excessive and toxic biomolecules, malfunction
organelles, etc. (Galluzzi et al., 2018). Multiple studies showed the
J Cell Physiol. 2019;234:19471–19479. wileyonlinelibrary.com/journal/jcp
during physiological and pathological conditions (Galluzzi, López‐Soto,
Kumar, & Kroemer, 2016). Briefly, cell death is divided into three major
categories including (1) type I programmed cell death or apoptosis; (2)
type II programmed cell death or autophagy; and (3) type III accidental
cell death or necrosis (Shakeri, Cicero, Panahi, Mohajeri, & Sahebkar,
2018). To effectively remedy melanoma, treatment strategies should be
focused on other cell death mechanisms instead of apoptosis. This is
due to the proliferative effect of apoptosis on neighboring surviving
cells, a phenomenon known as apoptosis‐induced proliferation (AiP). In
recent years, it has been shown that apoptosis can induce in a paracrine
manner a proliferative response in neighboring surviving cells. This
phenomenon has considerable clinical implications because apoptotic
treatments can induce cell proliferation and cancer stem cell recruit-
ment in different cancer types such as melanoma (Hurle, 2014). Donato
et al. (2014) demonstrated the induction of caspase 3‐dependent cell
death in melanoma cells leads to the proliferation of melanoma cells. It
was shown that caspase 3‐mediated dying melanoma cells stimulates
the growth and proliferation of melanoma cells through the secretion
of prostaglandin E2 (PGE2). In another study conducted by Roumane,
© 2019 Wiley Periodicals, Inc. | 19471
19472 | ASHRAFIZADEH
Berthenet, El Fassi, and Ichim (2018), the stimulatory effect of caspase‐
dependent cell death on the proliferation of melanoma cells was
confirmed. It was revealed that an alternative kind of cell death, known
as caspase‐independent cell death (CICD), has inhibitory effect on the
proliferation of melanoma cells and remarkably suppresses the
migration of tumor cells, whereas, apoptotic cell death is able to
induce the proliferation of living melanoma cells, requiring a novel and
revision of the therapeutic strategies based on other cell death
pathways.
In the present review, we focus on the influence of cell death
mechanisms involved in melanoma therapy and will discuss how to
sensitize melanoma cells with chemotherapeutics.
2 | AUT O PHA GY M A CH IN E
Autophagy was coined in 1950s following the mammalian cells
observation using electron microscopy (Mohammadinejad, Ahmadi,
Tavakol, & Ashrafizadeh, 2019). This mechanism is mainly divided into
three main categories including microautophagy, macroautophagy, and
chaperone‐mediated autophagy (Kimmelman & White, 2017; Shakeri
et al., 2018). Briefly, in microautophagy, cytoplasmic cargos are
engulfed in lysosomal or endosomal membranes, whereas chaperone‐
mediated autophagy as a selective degradation process special to
mammalian cells, targets proteins containing KFERQ‐like motif
(Cuervo & Wong, 2014). The most well‐known type of autophagy is
macroautophagy in which intracellular components are surrounded by
the double‐membrane compartments, known as autophagosome, and
then, their content releases into lysosome where the degradation and
recycling processes occur (Klionsky & Codogno, 2013). Noteworthy,
despite the great amount of investigations in neurological diseases
(Abdolmaleky et al., 2015; Faghihi et al., 2016; Tavakol et al., 2017;
Zendedel et al., 2012), impairment or decline in autophagy has been
observed in ageing and neurodegenerative diseases such as amyo-
trophic lateral sclerosis (Menzies, Fleming, & Rubinsztein, 2015).
Autophagy has dual effects on cells, it acts as both cell survival and
lethal mechanisms to modulate homeostasis in cells (White, 2016). In
other words, autophagy is activated under stress conditions such as
starvation and acidic pH microenvironment to guarantee cell survival
(Tavakol, 2014), because in physiological conditions, it acts at the
baseline level to prevent the accumulation of excessive biomolecules
and damaged cells and organelles. Autophagy performs through a
variety of proteins encoded by autophagy‐related genes (ATGs). It has
been reported that more than 30 ATGs are involved in autophagy
(Klionsky et al., 2011). Upon the insufficient level of energy (ATP
form), AMP‐activated protein kinase (AMPK) is activated that
consequently leads to autophagy induction. However, mammalian
target of rapamycin (mTOR) negatively is involved in autophagy
regulation, as well. Activation of mTORC1 inhibits autophagy and
under the lack of growth factors and/or amino acids, autophagy is
triggered due to the inhibition of mTORC1.
Nowadays, autophagy has attracted much attention owing to its
major role in cancer progression and therapy (Galluzzi et al., 2015).
ET AL.
The role of autophagy in cancer is sophisticated and is dependent to
the tumor type and driving oncogene (Nyfeler & Eng, 2016).
Previously, it was thought that autophagy has a remarkable tumor‐
suppressive role, whereas now it is believed that autophagy plays a
significant protumorigenic role in a number of cancers. However, the
stage of cancer dictates the role of autophagy as an antitumor or
protumorogenic mechanisms (Rabiee, Tavakol, Barati, & Joghataei,
2018). Several studies exhibit that autophagy can be considered as a
survival mechanism in cancer cells against therapies such as
chemotherapy and radiotherapy (Rebecca & Amaravadi, 2016).
Eventually, it promotes durability of cancer cells against apoptosis
(Fitzwalter et al., 2018). Thorburn et al. (2014) demonstrated that
following autophagy inhibition, proapoptotic protein PUMA (activa-
tor of apoptosis) increases. Thus, modulation of autophagy can be
considered as a promising strategy to diminish cancer progression.
3 | AN OIKIS
Anoikis was introduced for the first time in epithelial and endothelial cells
(Terasaki et al., 2018). It is a special type of apoptotic cell death resulting
from the lack of cell attachment to the extracellular matrix (ECM) or
adhesion to wrong locations, therefore, it mainly depends on the cell–
matrix interactions (Kakavandi, Shahbahrami, Goudarzi, Eslami, &
Faghihloo, 2018). Anoikis is critical for development and tissue home-
ostasis. It was demonstrated that this important pathway inhibits tumor
formation by neoplastic cells (Gilmore, 2005); however, tumor cells are
resistant to anoikis through TrkB (Mawji et al., 2007). To sum things up,
cell detachment from ECM leads to anoikis, cell proliferation in
inappropriate locations, and metastasis in long‐range organs (Chiarugi &
Giannoni, 2008; Frisch & Screaton, 2001). A number of intrinsic and
extrinsic signaling pathways are engaged with the activation of anoikis
and its progression (Grossmann, 2002). The intrinsic pathway mainly
crosses through the mitochondria. Briefly, following stress conditions
such as DNA damage and ER stress, Bax, and Bak are transmitted from
the cytosol to outer mitochondria membrane (OMM) and increases
mitochondrial permeabilization and cytochrome c release. Then, cyto-
chrome c forms apoptosome and as a consequence, apoptosis occurs
(Cohen, 1997). BH3‐only proteins are considered as the crucial mediators
during anoikis. Upon the cell‐ECM detachment, Bid, and Bam (members
of BH3‐only proteins) are activated and enhances the oligomerization of
Bax‐Bak inside the OMM (Taylor, Cullen, & Martin, 2008). However, Bad,
Bik, Bmf, Noxa, Puma, and Hrk are the other members of BH3‐only family
and indirectly are involved in the oligomerization of Bax‐Bak (Kuwana
et al., 2005). On the other hand, various death receptor transmembrane
proteins such as Fas receptor, TNFR1, and TNF‐related apoptosis
inducing ligand (TRAIL) receptor‐1 and ‐2 are engaged with the death
signaling pathways. Following the ligand binding, death‐inducing signaling
complex (DISC) is formed and it increases the activation of a number of
molecules including caspase‐8 through interplay with Fas‐associated
death domain protein (FADD). Finally, activation of caspase‐8 leads to
induction of caspase‐3, ‐6, and ‐7 and subsequently, cell death
(Mohammadinejad et al., 2018). It has been shown that upon the cel
ASHRAFIZADEH ET AL.
ECM detachment, Fas and Fas ligand are upregulated, demonstrating the
vital role of extrinsic pathway in anoikis execution (Aoudjit & Vuori,
2001).
Anoikis regulation is a crucial step in cancer therapy owing to its
critical role in cancer metastasis. In a study, Chen et al. (2018)
examined the effect of hepatocellular carcinoma‐related protein‐1
(HCRP‐1) on human colon cancer. Their results showed that HCRP‐1
inhibition is associated with tumor metastasis and it was found that
HCRP‐1 positively affects cell anoikis through Bim regulation.
Notably, the regulation of anoikis via HCRP‐1 can be considered as
a suitable strategy in colon cancer therapy. Taking everything into
account, these findings disclosed the major role of anoikis in tumor
metastasis and survival and shed light in cancer biology and therapy.
4 | NEC ROP TOSIS
Necroptosis was introduced in 2005 by Dagterev et al. (Li, Ning, Lou, &
Xu, 2018) as a new form of programmed cell death with similar
morphological characteristic to necrosis (Nikseresht, Khodagholi, &
Ahmadiani, 2018). It has some features of apoptosis and necrosis; for
example, it has morphological signs such as early disruption of plasma
membrane, translucent cytosol, enhanced cell size, and swollen
organelles (Ofengeim & Yuan, 2013) whereas it can be reversed like
apoptosis. Necroptosis is related to the various pathological conditions
such as ischemia/reperfusion (I/R) injury, nonalcoholic steatohepatitis,
sepsis, and atherosclerosis (Shan, Pan, Najafov, & Yuan, 2018). Although
it has a remarkable role in the efficacy of a number of cancer
therapeutics (Cruz, Qin, Stewart, & Chen, 2018), the belief is that
multiple signaling pathways are involved in activation of necroptosis
which are induced via numerous stimuli (Mohammadinejad et al., 2018).
Necroptosis is a caspase‐independent mechanism involving in the
activation of death receptors (Galluzzi, Kepp, Chan, & Kroemer, 2017).
During necroptosis, receptor interacting serine/threonine kinase 3
(PIRK3) and substrate mixed lineage kinase domain‐like (MLKL) play
significant roles in activation and execution of cell death, respectively
(Hadifar et al., 2018). Following the phosphorylation of MLKL by PIRK3,
MLKL is oligomerized and translocated to the plasma membrane, where
it enhances the permeability of membrane through the interaction with
a variety of phospholipids. This permeabilization is the major difference
between apoptosis and necrosis. To further clarify the necroptosis
phenomena and its difference with apoptosis and necrosis, it may be
said that apoptotic cells are surrounded by antigen‐presenting cells or
by adjacent cells, whereas in necroptosis, permeabilization prompts
releases of cytokines, and chemokines, resulting in the induction of
inflammation and immune response (Pasparakis & Vandenabeele, 2015).
5 | FERROPTOSIS
Another type of programmed cell death is ferroptosis with the
involvement of iron which was introduced by Dr. Brent R. Stockwell
in 2012 (Latunde‐Dada, 2017). This oxidative and iron‐mediated cell
| 19473
death is different from apoptosis, classic necrosis, autophagy, and
other types of cell death (Dixon et al., 2012). Intracellular ROS
production and lipid peroxides accumulation in cells are the
hallmarks of ferroptosis (Xie et al., 2016). In other words, ferroptosis
is activated through the high levels of iron in a process which known
as Fenton reaction (Yang et al., 2014) and through the ROS
accumulation resulting from impairment in cellular glutathione‐
dependent antioxidant defenses (Mawji et al. 2007). To sum things
up, ROS production, nicotinamide adenine dinucleotide phosphate
(NADPH)‐dependent lipid peroxidation and GSH depletion stimulate
ferroptosis (Yang et al., 2014). Furthermore, the family of mitogen‐
activated protein kinase (MAPK) including ERK, P38, and c‐Jun NH2‐
terminal kinase (JNK) are involved in ferroptosis. The morphological
characteristics of ferroptosis are including intact cell membrane,
ordinary volume of nucleus and dense miniature mitochondria which
are distinct from necrosis and apoptosis (Dolma, Lessnick, Hahn, &
Stockwell, 2003). It has been demonstrated that ferroptosis is
engaged with a great number of pathological conditions such as cell
death in kidney, brain and heart I/R injuries with the high levels of
glutamate (Angeli et al., 2014). However, the role of ferroptosis in
cancer is crucial and there are studies indicated in the tumor‐
suppressive role of ferroptosis (Yang et al., 2014). Taking everything
into account, the understanding of the ferroptosis mechanisms and
interactions in cancer is of interest in terms of developing novel
diagnostic and therapeutic approaches to adjust cell survival and
death in pathological conditions.
6 | ENDOPLASMIC RETICULUM STRESS
Endoplasmic reticulum (ER) as a largest organelle in eukaryotic cells, is a
double‐membrane compartment and is engaged with protein synthesis,
folding and maturation of approximately one‐third of the eukaryotic
proteins (Mollazadeh et al., 2018). However, ER is an organelle for Ca2+
storage and release, and lipid synthesis (Villalobos‐Labra, Subiabre,
Toledo, Pardo, & Sobrevia, 2018); therefore, ER homeostasis is vital for
cells. The imbalance between folding capacity of ER and newly
synthesized proteins leads to ER stress (Gallazzini & Pallet, 2018). Unfold
protein response (UPR) is one of the critical mechanisms involved in the
quality monitoring of ER. UPR promotes ER homeostasis through three
major signaling pathways which are integrated in the ER membrane:
Inositol‐requiring protein1 (IRE1), activating transcription factor 6 (ATF6),
and PRK‐like ER kinase (PERK; Walter & Ron, 2011). IRE1 interferes with
RNA (enhances RNA degradation) to diminish protein synthesis (Hollien
& Weissman, 2006). IRE1 indirectly participates in UPR and upon its
activation, it produces spliced form of X box‐binding protein 1 (sXBP1)
and then, sXBP1 activates genes that contribute to alleviating ER stress
to restore ER folding capacity (Acosta‐Alvear et al., 2007). On the other
hand, PERK is associated with transcription factors namely nuclear factor
erythroid 2‐related factor 2 (NRF2) and eukaryotic translation initiation
factor 2 (elF2α). NRF2 stimulates antioxidant proteins to regulate
oxidative stress whereas elF2α is involved in mRNA translation. Upon
elF2α inhibition, protein synthesis is diminished. Furthermore, during ER
19474 | ASHRAFIZADEH
F I G U R E 1 The induction of apoptosis, ER stress, anoikis, necroptosis, and autophagy using special drugs lead to melanoma inhibition. Noteworthy,
the inhibition and enhancement of autophagy have the two‐fold role in melanoma elimination. [Color figure can be viewed at wileyonlinelibrary.com]
stress, ATF6 translocates to Golgi apparatus to release transcription
factor (Shen, Chen, Hendershot, & Prywes, 2002). AFT6 targets UPR
proteins such as chaperons and also stimulates XBP1 and C/EBP
homologous protein (CHOP) genes (Yoshida et al., 2000).
It has been shown that ER stress stimulates autophagy and
apoptosis. ER‐associated degradation (ERAD) and UPR are the
quality control mechanisms of ER which contribute to ubiquition
and degradation of misfolded proteins via proteasome and autophagy
(Gu et al., 2017). At the mild and acute ER stress, autophagy is a
dominate process compared with the apoptosis whereas following
prolonged and exacerbate ER stress, apoptosis is triggered and cells
decide to suicide (B’chir et al., 2013). ER stress triggers autophagy
through the AMPK activation (Meares et al., 2011). As be mentioned
earlier, three major transmembrane proteins are involved in UPR
including IRE1, ATF6, and PERK. Furthermore, under ER stress, ATF6
positively affects the expression of death‐associated protein kinase 1
(DAPK1), consequently resulting in autophagy induction (Zalckvar
et al., 2009). Noteworthy, CHOP is involved in PERK and IRE1
pathways to induce apoptosis (Bu & Diehl, 2016). It has been
reported that protease, kinase, transcription factors, Bcl‐2 family
proteins as well as their modulators are involved in the triggering of
apoptosis via ER stress‐mediated UPR (Mollazadeh et al., 2018).
7 | MELA NOMA AND AU TOPH AGY
Nowadays, much investigations have been made to understand the
role of autophagy in cancer (Ahmadi, Mohammadinejad, & Ashrafiza-
deh, 2019; Mohammadinejad et al., 2019; Rabiee et al., 2018) and its
relation to other cell death mechanisms such as ferroptosis (Gao et al.,
2016). In a study, alisertib (ALS) was used to treat melanoma (Shang,
Yao, & Zhou, 2017). It was demonstrated that ALS in combination with
ET AL.
P38 MAPK‐selective inhibitor (SB202190) enhances apoptosis and
suppresses ALS‐induced autophagy. Noteworthy, autophagy inhibition
is associated with the high sensitization of melanoma cells to ALS‐
induced apoptosis. It has been reported that autophagy‐defective
tumors are not capable to recruit natural killer (NK) cells. Therefore,
autophagy targeting in melanoma cells may diminish tumor growth via
recruiting NK cells infiltration (Mgrditchian et al., 2017).
Meanwhile, Luan et al. (2017) investigated the effect of
polygonatum odoratum lectin (POL) on autophagy in melanoma cells.
Their results demonstrated that POL decreases melanoma cell
survival through downregulation of miR1290, leading to BECN1
upregulation and autophagy enhancement. Xiao, Diao, Liang, Peng,
and Zeng (2017) studied the effect of miR‐24‐1‐5p as an autophagy
inducer in melanoma cells. They found that miR‐24‐1‐5p remarkably
enhances the levels of LC3‐II/I ratio and beclin‐1 expression,
consequently resulting in autophagy promotion and the inhibition
of melanoma proliferation. Moreover, proopiomelanocortin (POMC)
induces melanoma cell elimination through the autophagy‐mediated
cell death (Wu, Tsai, Liu, Wu, & Tai, 2018; Figure 1).
8 | MELANO MA AND A NOIKIS
Anoikis resistant is a smart strategy in cancer cells to promote
metastasis (P. Gupta, N. Gupta, Fofaria, Ranjan, & Srivastava, 2019).
It is worth nothing that anoikis‐resistant melanoma cells are not
highly sensitive to chemotherapy (Tseng, Uen, Tseng, & Lee, 2017).
Hasnat, Pervin, Lim, and Lim (2015) investigated the effect of
apigenin on melanoma cells. They showed that apigenin decreases
the level of integrin proteins (inhibitors of anoikis) and suppresses
the phosphorylation of focal adhesion kinase (FAK) and extracellular
signal‐related kinase (ERK1/2), resulting in stimulation of anoikis in
ASHRAFIZADEH ET AL.
human melanoma cells (A2058 and A375 cell lines). Interestingly, it
has been shown that STAT3 enhances the invasiveness of melanoma
cells through anoikis inhibition (Fofaria & Srivastava, 2014). Beside of
STAT3, it has been reported that the upregulation of Timp1 makes
cells resistant to anoikis. In an effort in line with this statement, the
impact of Timp1 on melanoma cells was investigated (Toricelli, Melo,
Peres, Silva, & Jasiulionis, 2013). It was shown that Timp1 induces
anoikis resistance in melanoma cells through activating PI3‐k
signaling pathway. Furthermore, Goundiam, Nagel, and Vayssade
(2012) investigated the effect of Akt and RhoA inhibition on the
metastasis of highly metastatic B16F10 melanoma cells. They found
that the inhibition of Akt and RhoA decreases the expression of α5
integrin and inactivates focal adhesion kinase (FAK) in melanoma
cells, leading to the anoikis induction in anoikis‐resistant cells. Other
studies were in agreement with the effect of anoikis on metastasis
inhibition of melanoma cells (Boisvert‐Adamo & Aplin, 2006;
Boisvert‐Adamo, Longmate, Abel, & Aplin, 2009; Goldstein et al.,
2009; Zhang et al., 2011; Zhu et al., 2001; Figure 1).
9 | MELA NOMA AND NEC ROP TOSIS
As the necroptosis is a newly recognized pathway in cancer cells,
therefore, there are a few studies to in detail explain its role and
effect in melanoma. Kong, Lv, Yan, Chang, and Wang (2018)
examined the effect of a novel naphthyridine derivative, 3u, on
human melanoma A375 cells. It was shown that 3u stimulates
necroptosis at low concentrations through the upregulation of death
receptors and activation of caspase‐8. Furthermore, Basit et al.
(2017) exhibited the necroptosis induction in melanoma cells through
mitochondrial complex I inhibition. It has been shown that
necroptosis resistant in melanoma cells is related to the absence of
RIPK3 (Geserick et al., 2015). However, Hammerová, Uldrijan,
Táborská, Vaculová, and Slaninová (2012) investigated the effect of
sanguilutine (SL) on melanoma cell mortality through the autophagy
and necroptosis. It was found that SL stimulates caspase‐independent
non‐apoptotic cell death (necroptosis) whereas a combination of SL
and an autophagy inhibitor decreases the viability of melanoma cells,
demonstrating that SL can be considered as an ideal compound in the
induction of necroptosis in melanoma cells and is a beneficial
mediator to investigate the interplay between autophagy and
necroptosis (Figure 1).
10 | MELANOMA AND FERRO PTOSIS
Similar to necroptosis, ferroptosis is a newly introduced phenomenon in
melanoma and studies are increasing to manifest its role in melanoma.
In a study, Zhang et al. (2018) investigated the role of ferroptosis
regulation by miR‐9 in melanoma. They showed that miR‐9 decreases
the erastin‐ and RSL3‐induced ferroptosis in melanoma cells, demon-
strating that knocking down of miR‐9 induces ferroptosis in melanoma
cells. Furthermore, Luo et al. (2018) exhibited that miR‐137 negatively
| 19475
affect necroptosis in melanoma cells and also the inactivation of miR‐
137 enhances the antitumor activity of erastin by elevating ferroptosis.
Moreover, it was demonstrated that mitochondrial complex I inhibitor is
an important target in the induction of ferroptosis in melanoma cells
(Basit et al., 2017; Figure 1).
11 | M E L ANO M A AN D EN D O PL AS M I C
RE T I C U LU M S T R ES S
ER stress may be considered as a promising strategy to eliminate
melanoma cells. There are some pharmaceuticals to diminish
melanoma through the activation of ER stress‐induced apoptosis.
Honokiol‐mediated ER stress has been recognized to suppress the
growth and metastasis of melanoma (Chiu et al., 2019). It induces
apoptosis and inhibits epithelial‐mesenchymal transition (EMT) in
highly metastatic melanoma xenograft mouse model via ER stress.
Also, Heo, Kim, Hwang, Kang, and Choi (2018) investigated the effect
of resveratrol on ER stress‐induced apoptosis in A375SM malignant
melanoma cell line. They demonstrated that resveratrol suppresses
the growth of melanoma cells via the stimulation of ER stress through
the overexpression of elF2‐α and CHOP. Furthermore, the antitumor
effect of pinocembrin on melanoma cells is based on ER stress (Zheng
et al., 2018). It was exhibited that pinocembrin acts in a dose‐
dependent manner through IRE1a/Xbp1 pathway. Noteworthy, not
only ER stress induces apoptosis in melanoma cells but also, it sensitize
melanoma cells to chemotherapy (Ryabaya et al., 2018). It has been
demonstrated that the downregulation of ER stress chaperon 78 kDa
glucose‐regulated protein 78 (GRP78) prevents autophagy and
increases the effect of chemotherapy on melanoma cells. It has been
shown that bornyl cis‐4‐hydroxy cinnamate stimulates PERK and
elF2α pathways to activate ER stress‐apoptosis in melanoma cells
(Yang, Wu, Chang, Chiu, & Wu, 2018). Interestingly, Heo, Lee, Kim,
Hwang, and Choi (2018) conducted a comprehensive experiment on
the impacts of kaempferol, genistein, and 3,3'‐diinolylmethane on ER
stress‐induced apoptosis on A375SM melanoma cells. Their results
showed that these compounds increase the expression of elF2α and
CHOP to exert ER stress‐mediated apoptosis in melanoma cells.
Notwithstanding, mechano growth factor E peptide eliminates invasive
melanoma cells via inducing ER stress through the upregulation of cell
apoptosis‐related protein CHOP (He et al., 2018; Figure 1).
12 | CO N CL US I O N AND RE M AR K S
Melanoma as the most major skin malignancy has attracted much
attention, so far. To have a successful therapeutic strategy for melanoma
treatment, it requires an accurate understanding of the precise
mechanisms involved in the initiation and the progression of melanoma.
Recently, various cell death mechanisms beside of other conventional cell
death mechanisms such as apoptosis and necrosis have been identified
for the treatment of melanoma. The most major drawbacks of apoptosis
backs on the stimulatory effect of apoptosis‐dependent cell death
19476 | ASHRAFIZADEH
mechanisms on the growth and proliferation of surviving melanoma cells
and also the impairment effect of CICD mechanisms on these tumor cells.
Among those mechanisms, necroptosis, anoikis, ferroptosis, and autop-
hagy may be considered to have the remarkable modulator impact on
melanoma. Although at the first view it seems that the induction of cell
death mechanisms in melanoma cells overcome to its progression, but in
fact, the story is a bit complicated in tumors and resistant to cell death
mechanisms such as apoptosis, and anoikis leads to more investigation
with new approaches. The important note is related to the different
effects of chemotherapeutics associated with the different phases of
cancer and its invasiveness. It is interesting from one side, autophagy
inhibition causes apoptosis in melanoma cells, whereas from other side,
autophagy‐ defective tumors suffer from decreased recruiting of NK cells
infiltration. Moreover, there are some reports indicating the promising
outcomes in the elimination of tumor cells through the targeting of
autophagy mechanism. Notably, the most antimelanoma studies were in
agreement with the induction of autophagy through BECN1 upregulation,
increasing the levels of LC3‐II/I ratio. In fact, cancer cells are considerably
smart and although are disconnected from the ECM and neighbor cells
but they do not become home sick and are resistant to anoikis and less
response to the chemotherapeutics. Noteworthy, the inhibition of AKT
and RhoA may be considered a promising strategy to induce anoikis in
anoikis‐resistant melanoma cells. Besides, the necroptosis resistant
melanoma is in part due to the absence of RIPK3 and is modulated
through some pharmaceuticals such as naphthyridine derivative.
Furthermore, it seems that knocking down of miR‐9 and 137 is a
promising strategy to induce ferroptosis and melanoma cell death. Taking
everything into account, designing of a successful strategy to eliminate
cancer, needs to consider all aspects of the problem and also requires the
use of all cell death mechanisms.
CO NFLICT OF I NTERE STS
Authors declare that they have no conflict of interests.
FUNDING
There was no finding source to support the manuscript.
A UT HO RS CO NT RIB UT ION S
MA conducted the manuscript and wrote the introduction, “Melano-
ma and necroptosis”, “Melanoma and ferroptosis,” and conclusion
section. RM wrote the “Autophagy” and “Induction of autophagy and
apoptosis via endoplasmic reticulum stress” sections. ST scientifically
edited the manuscript and wrote the abstract and “Melanoma and
autophagy” section. ZA wrote the “Anoikis”, “Necroptosis” and
“Ferroptosis” sections. SR wrote the “Endoplasmic reticulum stress”
and “Induction of autophagy and apoptosis via endoplasmic reticulum
stress” sections. MK wrote the “Melanoma and anoikis” section.
ET AL.
ORCI D
Milad Ashrafizadeh http://orcid.org/0000-0001-6605-822X
Shima Tavakol http://orcid.org/0000-0002-8531-7650
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