Abstract
The cell cycle involves a network of proteins that modulate the sequence and timing of proliferation events. Unregulated proliferation is the most fundamental hallmark of cancer; thus, changes in cell cycle control are at the heart of malignant transformation processes. Several cellular processes can interfere with the cell cycle, including autophagy, the catabolic pathway involved in degradation of intracellular constituents in lysosomes. According to the mechanism used to deliver cargo to the lysosome, autophagy can be classified as macroautophagy (MA), microautophagy (MI), or chaperone-mediated autophagy (CMA). Distinct from other autophagy types, CMA substrates are selectively recognized by a cytosolic chaperone, one-by-one, and then addressed for degradation in lysosomes. The function of MA in cell cycle control, and its influence in cancer progression, are already well-established. However, regulation of the cell cycle by CMA, in the context of tumorigenesis, has not been fully addressed. This review aims to present and debate the molecular mechanisms by which CMA can interfere in the cell cycle, in the context of cancer. Thus, cell cycle modulators, such as MYC, hypoxia-inducible factor-1 subunit alpha (HIF-1α), and checkpoint kinase 1 (CHK1), regulated by CMA activity will be discussed. Finally, the review will focus on how CMA dysfunction may impact the cell cycle, and as consequence promote tumorigenesis.
Highlights
Cancer cells usually present a variety of impaired cellular mechanisms as a consequence of genomic instability
The substrate interacts with the cytosolic tail of the lysosome-associated membrane protein type 2A (LAMP-2A), which acts as a receptor for the chaperone-mediated autophagy (CMA) pathway [36,38]
Through the inhibition of cyclin D1, a protein essentially involved in cell cycle progression by binding to CDK4/6, CMA is potentially intricate in G0/gap 1 (G1) phase progress control in hepatocellular carcinoma cells [83]
Summary
Cancer cells usually present a variety of impaired cellular mechanisms as a consequence of genomic instability. The CMA motif is based on the charge of the amino acids, so in certain cases, it is possible to obtain a recognizable motif—even if it is incomplete—through post-translational modifications, such as phosphorylation or acetylation [37] After this targeting step, the substrate interacts with the cytosolic tail of the lysosome-associated membrane protein type 2A (LAMP-2A), which acts as a receptor for the CMA pathway [36,38]. The substrate interacts with the cytosolic tail of the lysosome-associated membrane protein type 2A (LAMP-2A), which acts as a receptor for the CMA pathway [36,38] This protein is a spliced variant of the Lamp gene. The substrate reaches the lysosomal matrix, where it undergoes a complete degradation, and LAMP-2A is rapidly disassembled from the translocation complex into monomers, allowing the binding of new substrates [39]
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