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Review
. 2017 May 3;8(31):51970-51985.
doi: 10.18632/oncotarget.17583. eCollection 2017 Aug 1.

Chaperone-mediated autophagy substrate proteins in cancer

Ying Tang #  1 , Xiong-Wen Wang #  1 , Zhan-Hua Liu  1 , Yun-Ming Sun  2 , Yu-Xin Tang  2 , Dai-Han Zhou  1
Affiliations
Review

Chaperone-mediated autophagy substrate proteins in cancer

Ying Tang et al. Oncotarget. .

Abstract

All intracellular proteins undergo continuous synthesis and degradation. Chaperone-mediated autophagy (CMA) is necessary to maintain cellular homeostasis through turnover of cytosolic proteins (substrate proteins). This degradation involves a series of substrate proteins including both cancer promoters and suppressors. Since activating or inhibiting CMA pathway to treat cancer is still debated, targeting to the CMA substrate proteins provides a novel direction. We summarize the cancer-associated substrate proteins which are degraded by CMA. Consequently, CMA substrate proteins catalyze the glycolysis which contributes to the Warburg effect in cancer cells. The fact that the degradation of substrate proteins based on the CMA can be altered by posttranslational modifications such as phosphorylation or acetylation. In conclusion, targeting to CMA substrate proteins develops into a new anticancer therapeutic approach.

Keywords: Warburg effect; cancer; chaperone-mediated autophagy; glycolysis; substrate proteins.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors have declared no potential conflicts of interest.

Figures

Figure 1
Figure 1. The process of CMA: (1) Recognizing substrate proteins and targeting them to lysosome; (2) Binding and unfolding substrate proteins; (3) Translocation into lysosomes; (4) Degradation by lysosome hydrolytic enzymes
Figure 2
Figure 2. CMA substrate proteins in cancer: the acetylated PKM2 displays a stronger interaction with HSC70
Phosphorylation translocates Rnd3 from membrane to cytosol and promotes Rnd3 interaction with CMA. Unphosphorylated PED binds HSC70 and degradation by CMA. However, phosphorylated PED binds to HSC70 at a low level (dotted line). Misfolded N-CoR is associated with HSC70 and degraded through the CMA. The degradation of mutant TP53 is mediated by the CMA and the degradation of TP53 through macroautophagy.
Figure 3
Figure 3. A schematic illustration of CMA substrate proteins involve in Warburg effect: glucose translocation through the plasma-membrane by glucose transporters (GLUT1/2) is rapidly phosphorylated to glucose-6-phosphate (G6P) by HK2
PKM2 dimers and tetramers possess low and high levels of pyruvate kinase activity, respectively. PKM2 dimer redirects the conversion of pyruvate to lactate; the PKM2 tetramer promotes the oxidative phosphorylation through the mitochondria respiratory chain. The Warburg effect describes the enhanced conversion of glucose to lactate by tumor cells, even in the presence of adequate oxygen that would ordinarily be used for oxidative phosphorylation.
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