The Role of Chaperone-Mediated Autophagy in Cell Cycle Control and Its Implications in Cancer

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.

Beyond Self-Recycling: Cell-Specific Role of Autophagy in Atherosclerosis

“…There are three classes of autophagy, macro-autophagy, micro-autophagy and chaperone-mediated autophagy, which differ primarily through the method of cargo delivery to the lysosome for degradation. The mechanisms of micro-autophagy (where cytoplasmic components are directly engulfed in lysosomes) and chaperone-mediated autophagy (which involves chaperones to transport proteins and/or nucleic acids through the lysosomal membrane) have been extensively reviewed elsewhere [ 40 , 41 , 42 ]. This review will focus on macro-autophagy, commonly referred to as ‘autophagy’ [ 30 ].…”

The Multifaceted Role of CMA in Glioma: Enemy or Ally?

“…For instance, some proteins act as tumor promoters (AF1Q, Vav1, PKM2, Eps8, mutant p53, HK2) and other proteins play a role as tumor suppressors (unphosphorylated PED, Rnd3) [ 15 ]. Considering all this, even if indirect, it is important to discuss the role of CMA in the modulation of tumor cell survival or death [ 6 ].…”

“…CMA blockage has been described as a driver for resistance to TMZ mainly because of its role in the modulation of several factors involved in glucose metabolism and in the regulation of transcription, translation, and cell cycle control [ 6 ]. Among them, HIF-1α, one of the factors associated with glioma malignancy, can be also degraded by CMA [ 54 ].…”

“…This machinery includes the multi-enzyme proteasome system and all the different displays of autophagic phenomena. It has been shown that it is a highly specific mechanism behaving as a biosensor of cellular stress and contributing to cell adaptation to external stimuli, such as nutrient deprivation or oxidative stress and cell damage, and that it is finely regulated by multiple mechanisms [ 6 ].…”

The p62/Keap1/Nrf2 axis in the control of C-2 induced human gastric cancer cell death switching between autophagy and apoptosis

“…Autophagy plays an important role in regulating cell homeostasis, mediating the removal of dysfunctional or damaged organelles, which are digested for the needs of cell metabolism [9,10]. According to physiological function of autophagy and the process of "cargo" to be degraded, autophagy are divided into three different types: microautophagy, molecular chaperone-mediated autophagy and macroautophagy [11,12]. In this article, the term "autophagy" refers to macroautophagy.…”