br The Molecular Machinery of

The Molecular Machinery of Autophagy and Regulation by Sphingolipids
Sphingolipid-Mediated Autophagy in Cancer: Dr. Jekyll and Mr. Hyde Autophagy is an evolutionarily conserved stress response that typically promotes survival and antagonizes apoptosis. However, excessive autophagy was found to induce cell death accompanied by the accumulation of autophagic structures but morphologically distinct from apoptosis or necrosis, thereby coining the term “autophagic cell death” or “type II cell death.” Autophagy-dependent cell death is defined as a form of regulated cell death (RCD) that is dependent on the autophagic machinery (Galluzzi et al., 2018). In addition to cell killing by excessive cytoplasmic degradation, autophagy also initiates apoptosis. As many autophagy proteins have autophagy-independent functions and several pharmacological inhibitors of autophagy have off-target effects, two or more components of the autophagic machinery should be shown to be required prior to labeling cell death as autophagy dependent. Furthermore, the term should be avoided in instances where autophagy is activated alongside RCD or in cases where autophagy merely facilitates the execution of RCD (Galluzzi et al., 2018). Autophagy has multiple faces in cancer, as it can: (1) promote cancer cell survival, (2) induce an alternative mechanism of cell death, or (3) initiate the apoptotic cascade. Here, we will summarize how sphingolipid-mediated autophagy drives cancer cell survival as “Dr. Jekyll” but can be unleashed for cancer cell death as “Mr. Hyde.”
Conclusion and Future Directions In this chapter, we aimed to provide a comprehensive review of sphingolipids in the regulation of autophagosome biogenesis, autophagic flux, and autophagic outcome (survival or death) in cancer. As a natural caveat to this approach, the data were collected using a range of cell lines and experimental conditions. This is noteworthy because cell line–dependent protein expression may drive autophagic response to sphingolipids. For example, extracellular S1P inhibits autophagy in S1PR3-expressing HL-60 leukemia SB-715992 synthesis but promotes autophagy in S1PR5-expressing PC3 prostate cancer cells (Chang et al., 2009, Taniguchi et al., 2012). Moreover, different cancer cell lines have varying degrees of autophagy dependence; for example, K-Ras mutations are associated with high autophagy dependence (Guo et al., 2011, Kim, J.H. et al., 2011, Kim, M.J. et al., 2011). Despite these limitations, we can begin to appreciate the importance of sphingolipids in autophagy, as sphingolipid metabolism regulates each step of autophagosome biogenesis and maturation. Moreover, as the same sphingolipid influences autophagy at multiple steps, other factors such as intracellular location, local metabolism, and/or species-dependent effects (i.e., acyl chain length, saturation) are likely to be involved, as is suggested by the role of mitochondrial localized C18-ceramide in lethal mitophagy (Sentelle et al., 2012). Continued investigation can begin to dissect some intriguing, but unanswered questions, including:
Introduction
Autophagy-associated hematopoiesis and hematological pathologies
Pharmacological modulators of autophagy for the treatment of hematological disorders
Conclusion
Introduction Autophagy and apoptosis, two distinct self-destructive processes, control the turnover of cytoplasmic organelles and entire cells, respectively [1]. Autophagy, or self-eating, is an evolutionarily conserved catabolic degradation process in which cytoplasmic contents, such as misfolded cellular proteins and damaged organelles, are engulfed by double-membrane autophagosomes and degraded in autolysosomes after the fusion of autophagosomes and lysosomes [2]. Apoptosis, or self-killing, is a well-characterized form of programmed cell death and involves the sequential activation of the caspase cascade and the activation of catabolic hydrolases that consume cellular structures and organelles, leading to the demolition of whole cells [3]. The crosstalk between autophagy and apoptosis, particularly the upstream signaling cascades, is multifaceted and complicated and has become a burgeoning area of research. Generally, the induction of autophagy suppresses the apoptotic process, and the activation of apoptosis-associated caspases shuts down the process of autophagy [1,[4], [5], [6]]. Elucidating the molecular mechanism of the crosstalk between these two processes will advance the therapeutic applications of autophagy regulation for treating cancer and other diseases.