LAMP2A overexpression in breast tumors promotes cancer cell survival via chaperone-mediated autophagy

Saha, Tapas Kumar

doi:10.4161/auto.21654

Cited by 133 publications

(149 citation statements)

References 53 publications

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“…In summary, the results of this research confirm a previously little-known cross-talk between macroautophagy and CMA in lymphoma Raji cells facing different stressors, and these findings must be helpful to understanding the characteristics, compensatory mechanisms and answer mode of different autophagic pathways in cancer cells, which may be very important and promising to the development of interventions targeting regulate one form of autophagy for potential targeting therapeutic purposes in human diseases, such as cancer or neurodegenerative disorders (Kon et al, 2011;Saha, 2012;Xilouri et al, 2013). Up-regulation of one autophagic pathways after the failure of another particular form of autophagy can be the basis for future therapeutic interventions to preserve normal cellular function in these pathologies.…”

Section: Discussionsupporting

confidence: 72%

Ebb-and-Flow of Macroautophagy and Chaperone-Mediated Autophagy in Raji Cells Induced by Starvation and Arsenic Trioxide

Wei²,

Chen³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Autophagy is crucial in the maintenance of homeostasis and regenerated energy of mammalian cells. Macroautophagy and chaperone-mediated autophagy(CMA) are the two best-identified pathways. Recent research has found that in normal cells, decline of macroautophagy is appropriately parallel with activation of CMA. However, whether it is also true in cancer cells has been poorly studied. Here we focused on crosstalk and conversion between macroautophagy and CMA in cultured Burkitt lymphoma Raji cells when facing serum deprivation and exposure to a toxic compound, arsenic trioxide. The results showed that both macroautophagy and CMA were activated sequentially instead of simultaneously in starvation-induced Raji cells, and macroautophagy was quickly activated and peaked during the first hours of nutrition deprivation, and then gradually decreased to near baseline. With nutrient deprivation persisted, CMA progressively increased along with the decline of macroautophagy. On the other hand, in arsenic trioxide-treated Raji cells, macroautophagy activity was also significantly increased, but CMA activity was not rapidly enhanced until macroautophagy was inhibited by 3-methyladenine, an inhibitor. Together, we conclude that cancer cells exhibit differential responses to diverse stressor-induced damage by autophagy. The sequential switch of the first-aider macroautophagy to the homeostasis-stabilizer CMA, whether active or passive, might be conducive to the adaption of cancer cells to miscellaneous intracellular or extracellular stressors. These findings must be helpful to understand the characteristics, compensatory mechanisms and answer modes of different autophagic pathways in cancer cells, which might be very important and promising to the development of potential targeting interventions for cancer therapies via regulation of autophagic pathways.

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Section: Discussionsupporting

confidence: 72%

Ebb-and-Flow of Macroautophagy and Chaperone-Mediated Autophagy in Raji Cells Induced by Starvation and Arsenic Trioxide

Wei²,

Chen³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…7 Thus, CMA inhibition in malignant cells lowers cellular proliferation and reduces tumorigenic and metastatic capacity. 7,19 Later reports have confirmed this dependence on CMA for cancer cell growth and attribute it to a diversity of mechanisms including: protection against oxidative damage, 19 removal of negative regulators of cell proliferation 20 and antioncogenes 21 or maintenance of the metabolic switch favorable for cancer cell growth. 22,23 However, the role of CMA on early stages of tumor development such as transformation of normal cells into cancerous cells has not been elucidated.…”

Section: Introductionmentioning

confidence: 93%

Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation

2017

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Chaperone-mediated autophagy (CMA), a selective form of protein lysosomal degradation, is maximally activated in stress situations to ensure maintenance of cellular homeostasis. CMA activity decreases with age and in several human chronic disorders, but in contrast, in most cancer cells, CMA is upregulated and required for tumor growth. However, the role of CMA in malignant transformation remains unknown. In this study, we demonstrate that CMA inhibition in fibroblasts augments the efficiency of MYC/c-Mycdriven cellular transformation. CMA blockage contributes to the increase of total and nuclear MYC, leading to enhancement of cell proliferation and colony formation. Impaired CMA functionality accentuates tumorigenesis-related metabolic changes observed upon MYC-transformation. Although not a direct CMA substrate, we have found that CMA regulates cellular MYC levels by controlling its proteasomal degradation. CMA promotes MYC ubiquitination and degradation by regulating the degradation of C330027C09Rik/KIAA1524/CIP2A (referred to hereafter as CIP2A), responsible for MYC stabilization. Ubiquitination and proteasomal degradation of MYC requires dephosphorylation at Ser62, and CIP2A inhibits the phosphatase responsible for this dephosphorylation. Failure to degrade CIP2A upon CMA blockage leads to increased levels of phosphorylated MYC (Ser62) and to stabilization of this oncogene. We demonstrate that this phosphorylation is essential for the CMA-mediated effect, since specific mutation of this site (Ser62 to Ala62) is enough to normalize MYC levels in CMA-incompetent cells. Altogether these data demonstrate that CMA mitigates MYC oncogenic activity by promoting its proteasomal degradation and reveal a novel tumor suppressive role for CMA in nontumorigenic cells.

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“…While CMA deficiency characterizes many neurodegenerative pathologies, upregulation of CMA has been linked to the survival and proliferation of cancer cells [17,35,64]. Examination of CMA activity in a wide array of cancer cell lines and human tumor biopsies has demonstrated a consistent increase in basal CMA activity [35].…”

Section: Abnormally Enhanced Cma and Cancermentioning

confidence: 99%

“…Lastly, it is possible that in other tumors, part of the negative consequences of CMA blockage are due to reduced quality control. While in many cancer cell types, prolonged blockage of CMA elicits upregulation of the ubiquitin proteasome system (UPS), thus preventing accumulation of damaged substrates normally degraded by CMA [35], in other types of cancers, accumulation of oxidized and misfolded proteins has been proposed to underlie the toxic effect of CMA blockage [23,64]. The upregulated CMA in these latter cells helps to ameliorate intracellular stress and promotes the activation of oncogenic survival pathways [23].…”

Section: Abnormally Enhanced Cma and Cancermentioning

confidence: 99%

Chaperone-mediated autophagy: roles in disease and aging

2013

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This review focuses on chaperone-mediated autophagy (CMA), one of the proteolytic systems that contributes to degradation of intracellular proteins in lysosomes. CMA substrate proteins are selectively targeted to lysosomes and translocated into the lysosomal lumen through the coordinated action of chaperones located at both sides of the membrane and a dedicated protein translocation complex. The selectivity of CMA permits timed degradation of specific proteins with regulatory purposes supporting a modulatory role for CMA in enzymatic metabolic processes and subsets of the cellular transcriptional program. In addition, CMA contributes to cellular quality control through the removal of damaged or malfunctioning proteins. Here, we describe recent advances in the understanding of the molecular dynamics, regulation and physiology of CMA, and discuss the evidence in support of the contribution of CMA dysfunction to severe human disorders such as neurodegeneration and cancer.

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LAMP2A overexpression in breast tumors promotes cancer cell survival via chaperone-mediated autophagy

Cited by 133 publications

References 53 publications

Ebb-and-Flow of Macroautophagy and Chaperone-Mediated Autophagy in Raji Cells Induced by Starvation and Arsenic Trioxide

Ebb-and-Flow of Macroautophagy and Chaperone-Mediated Autophagy in Raji Cells Induced by Starvation and Arsenic Trioxide

Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation

Chaperone-mediated autophagy: roles in disease and aging

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