Chonnam Med J.  2018 Sep;54(3):135-142. 10.4068/cmj.2018.54.3.135.

Melanoma Cell Death Mechanisms

• Broussard
• Howland A
• Ryu S
• Song K
• Norris D
• Armstrong
• Song PI

• KMID: 2420880
• DOI: http://doi.org/10.4068/cmj.2018.54.3.135

Abstract

Over recent years, several new molecular and immunogenic therapeutic approaches to melanoma treatment have been approved and implemented in clinical practice. Mechanisms of resistance to these new therapies have become a major problem. Mutation-specific pharmacotherapy can result in simultaneous emergence of resistant clones at many separate body sites despite an initially positive therapeutic response. Additionally, treatments aimed at inducing apoptosis are subject to resistance due to escape through other known mechanisms of regulated cell death (RCD). In this review, we discuss the complexity in pharmacological manipulation of melanoma with c-Kit, BRAF, MEK, and/or mTOR mutant cell lines. This study also addresses melanoma evasion of cell death through modalities of RCD such as apoptosis, autophagy, and necroptosis. This study also examines new combination therapies which have been approved to target both cell cycle dysregulation and cell death pathways. Lastly, we recognize the importance of immunomodulation though manipulation of the body's natural killing mechanisms with CTLA4, PD1, and CSF1 inhibition. As we begin to recognize tumor cell activation of alternate pathways, evasion of programmed cell death, and manipulation of the tumor microenvironment, it is increasingly important to grasp the complexity of personalized therapy in melanoma treatment.

Keyword

Melanoma; Autophagy; Apoptosis; CTLA4 protein, human; TOR Serine-Threonine Kinases

MeSH Terms

Apoptosis
Autophagy
Cell Cycle
Cell Death*
Cell Line
Clone Cells
Drug Therapy
Hand Strength
Homicide
Humans
Immunomodulation
Melanoma*
TOR Serine-Threonine Kinases
Tumor Microenvironment
United Nations
TOR Serine-Threonine Kinases

Figure

• 

  FIG. 1 Regulated Cell Death (RCD) in Melanoma: Apoptosis, Autophagy, and Necroptosis. Classification of basic Caspase-dependent and Caspase-independent cell death processes and key players.21222529

• 

  FIG. 2 Mechanisms of Autophagy Initiation in Melanoma: (A) Macroautophagy. Initiation of autophagosome formation requires the ULK1-Atg13-FIP200 complex and Beclin1-class III PI3K complexes along with two conjugation systems, Atg12-Atg5-Atg16 and Atg8-PE. LC3 proteolysis and lipidation is involved in the elongation phase. Cytoplasmic matter is engulfed by the phagophore surrounded by a double-membrane vesicle referred to as the autophagosome. Next, the autophagosome fuses with a lysosome to form an autolysosome. The contents within the autolysosome are degraded by the lysosome. Low ATP levels and hypoxia induce autophagy. Conversely, mTOR is activated in a nutrient rich environment which ultimately inhibits autophagy through suppression of ULK1 activity. Insulin and other growth factors can also stimulate phosphorylation and activation of mTOR. (B) Microautophagy. Cellular contents are directly sequestered into the lysosome by self-invagination of lysosomal membranes. (C) Chaperone-mediated autophagy. Hsc70 or Hsc90 chaperone facilitates binding of cytosolic proteins to LAMP2A receptor resulting in lysosomal translocation and internalization.252627

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