Abstract
The transcriptional regulation of autophagy‐lysosomal pathway adapts to cellular stress and enables advanced cancer cells survive. This pathway plays an oncopromoting or oncosuppressing role, depending on context‐dependent stresses and treatment resistance. It remains controversial whether this pathway represents a target for drugs, although autophagy‐lysosomal inducers and inhibitors have been tested in clinical trials for cancer treatment. Therefore, identifying the transcriptional regulators of autophagy‐lysosomal pathway may lead to the development of effective cancer treatment and the improvement of the existing targeted cancer therapies. In this review, we summarize findings from several published studies on transcriptional regulation of autophagy‐lysosomal pathway in cancer biology, and evaluate its functional role as a therapeutic target.
Highlights
The metabolic reprogramming maintains the survival, proliferation, and metastasis of cancer cells in adverse microenvironmental conditions
During autophagy, aggregated and misfolded proteins and damaged organelles are delivered to the lysosome in double-membrane vesicles called the autophagosomes, which fuse with lysosomes and form single-membrane vesicles called autolysosomes
We focus on the transcriptional regulation of autophagy-lysosomal function and regulation in tumorigenesis
Summary
The metabolic reprogramming maintains the survival, proliferation, and metastasis of cancer cells in adverse microenvironmental conditions. Some tumor cells (including activated Myc) depend on glutaminolysis for survival and upregulate glutamine transporters and enzymes.[9] Basal autophagy can be promoted by ammonia produced by glutaminolysis, protecting cancer cells from TNFα-induced apoptosis and limiting proliferation under stressful conditions.[10] autophagy can interact with other pathways such as Ras and p53 in tumor cells to regulate tumorigenesis. The regulation of mTORC1 by p62 promoted cell proliferation in vitro and tumor growth in vivo.[15] mTOR regulated V-ATPase, a critical component of the late endosome/lysosome, through a transcription factor EB (TFEB) in renal cancer.[16] That is to say, there is a regulatory network linking an oncogenic transcription factor TFEB to mTORC1 and lysosomal biogenesis, which allows autophagy to act as an oncosuppressor or oncopromoter. Many cancer therapeuties induce autophagy because they cause metabolic stress (2-deoxyglucose, angiogenesis inhibitors), cellular damage (cytotoxic chemotherapy), or mimic factor deprivation/starvation to block growth signaling pathways (targeted noncytotoxic, kinase inhibitors). P53 can activate the following encoding genes: β1 and β2 AMPK subunits, tuberous sclerosis 2 (TSC2), phosphatase and tensin homolog (PTEN), sestrin 1 and 2, and insulin-like growth factor binding protein 3 (IGFBP3), all of which functionally antagonize the autophagy-suppressive functions of mTOR. p53-inducible pro-apoptotic members of the BCL-2 protein family, such as BAX, BAD and BBC3, can stimulate autophagy by preventing inhibitory interactions of Beclin
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