Role of Autophagy in Cancer: Management of Metabolic Stress

Jin, Shengkan; White, Eileen

doi:10.4161/auto.3269

Cited by 364 publications

(276 citation statements)

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“…This necrosis in tumors is associated with inflammation and enhancement of tumor growth, due to the survival of a small population of surviving, but injured, cells in a microenvironment that favors oncogenesis. 39 Moreover, recent studies have suggested that autophagy is also an important mediator in the invasion of cancer cells. For example, autophagy accelerates the invasion of cancer cells during starvation or hypoxia.…”

Section: Discussionmentioning

confidence: 99%

MIR517Cinhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

Xiao

Liu

et al. 2015

Autophagy

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(2015) MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation, Autophagy, 11:12, 2213-2232, DOI: 10.1080/15548627.2015 LG, low glucose; MAP1LC3B/LC3B, microtubuleassociated protein 1 light chain 3B; MU, mutation; NC, negative control; NSC, neural stem cell; oe, overexpressing; OS, overall survival; PFS, progression-free survival; qRT-PCR, quantitative real-time reverse transcription polymerase chain reaction; SNAI2, Slug (snail family zinc finger 2); SNAI1, snail (snail family zinc finger 1); TEM, transmission electron microscopy; TMZ, temozolomide; VIM, vimentin; WT, wild type; ZEB1, zinc finger E-box binding homeobox 1.The epithelial-to-mesenchymal (-like) transition (EMT), a crucial embryonic development program, has been linked to the regulation of glioblastoma (GBM) progression and invasion. Here, we investigated the role of MIR517C/miR-517c, which belongs to the C19MC microRNA cluster identified in our preliminary studies, in the pathogenesis of GBM. We found that MIR517C was associated with improved prognosis in patients with GBM. Furthermore, following treatment with the autophagy inducer temozolomide (TMZ) and low glucose (LG), MIR517C degraded KPNA2 (karyopherin alpha 2 [RAG cohort 1, importin alpha 1]) and subsequently disturbed the nuclear translocation of TP53 in the GBM cell line U87 in vitro. Interestingly, this microRNA could inhibit autophagy and reduce cell migration and infiltration in U87 cells harboring wild-type (WT) TP53, but not in U251 cells harboring mutant (MU) TP53. Moreover, the expression of epithelial markers (i.e., CDH13/T-cadherin and CLDN1 [claudin 1]) increased, while the expression of mesenchymal markers (i.e., CDH2/N-cadherin, SNAI1/Snail, and VIM [vimentin]) decreased, indicating that the EMT status was blocked by MIR517C in U87 cells. Compared with MIR517C overexpression, MIR517C knockdown promoted infiltration of U87 cells to the surrounding structures in nude mice in vivo. The above phenotypic changes were also observed in TP53 +/+ and TP53 -/-HCT116 colon cancer cells. In summary, our study provided support for a link between autophagy and EMT status in WT TP53 GBM cells and provided evidence for the signaling pathway (MIR517C-KPNA2-cytoplasmic TP53) involved in attenuating autophagy and eliminating the increased migration and invasion during the EMT.

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Section: Discussionmentioning

confidence: 99%

MIR517Cinhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

Xiao

Liu

et al. 2015

Autophagy

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“…Autophagy is induced by conditions causing nutrient/energy depletion, cellular damage, and stress, which plays an important role not only in cancer development, but also in cancer treatment (38,39). An extensive literature documents the prosurvival functions of autophagy, but there are cases where autophagy appears to have a pro-death role (40,41).…”

Section: Discussionmentioning

confidence: 99%

Role of Autophagy in Cisplatin Resistance in Ovarian Cancer Cells

Wang

2014

Journal of Biological Chemistry

234

179

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Background:The contribution of autophagy to acquired cisplatin resistance in ovarian cancer has not been studied. Results: Cisplatin treatment activates ERK and subsequently promotes autophagy and counteracts cisplatin-induced cell death. Inhibition of autophagy enhances cisplatin sensitivity. Conclusion: Cisplatin-induced autophagy contributes to cisplatin resistance. Significance: Targeting autophagy may overcome cisplatin resistance.

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“…18 Nevertheless, recent evidence brought into question whether autophagy is involved in tumor progression or tumor suppression. 16,19,24,26,29 With respect to the relationship between TMZ and autophagy, TMZ treatment of GFP-LC3-overexpressing cells resulted in an increase in autophagosome formation. 18 However, bafilomycin A, a vesicular type proton-pump inhibitor that prevents the maintenance of the lysosomal acidic environment and inhibits autophagy clearance, enhanced TMZ cytotoxicity in glioma cells.…”

Section: Discussionmentioning

confidence: 99%

Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blocking autophagy

Golden

Cho²,

Jahanian

et al. 2014

FOC

153

117

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Object In a recent clinical trial, patients with newly diagnosed glioblastoma multiforme benefited from chloroquine (CQ) in combination with conventional therapy (resection, temozolomide [TMZ], and radiation therapy). In the present study, the authors report the mechanism by which CQ enhances the therapeutic efficacy of TMZ to aid future studies aimed at improving this therapeutic regimen. Methods Using in vitro and in vivo experiments, the authors determined the mechanism by which CQ enhances TMZ cytotoxicity. They focused on the inhibition-of-autophagy mechanism of CQ by knockdown of the autophagy-associated proteins or treatment with autophagy inhibitors. This mechanism was tested using an in vivo model with subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ. Results Knockdown of the autophagy-associated proteins (GRP78 and Beclin) or treatment with the autophagy inhibitor, 3-methyl adenine (3-MA), blocked autophagosome formation and reduced CQ cytotoxicity, suggesting that autophagosome accumulation precedes CQ-induced cell death. In contrast, blocking autophagosome formation with knockdown of GRP78 or treatment with 3-MA enhanced TMZ cytotoxicity, suggesting that the autophagy pathway protects from TMZ-induced cytotoxicity. CQ in combination with TMZ significantly increased the amounts of LC3B-II (a marker for autophagosome levels), CHOP/GADD-153, and cleaved PARP (a marker for apoptosis) over those with untreated or individual drug-treated glioma cells. These molecular mechanisms seemed to take place in vivo as well. Subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ displayed higher levels of CHOP/GADD-153 than did untreated or individual drug-treated tumors. Conclusions Taken together, these results demonstrate that CQ blocks autophagy and triggers endoplasmic reticulum stress, thereby increasing the chemosensitivity of glioma cells to TMZ.

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Role of Autophagy in Cancer: Management of Metabolic Stress

Abstract: Previously published online a an Autophagy E-publication:

Cited by 364 publications

References 26 publications

MIR517Cinhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

MIR517Cinhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

Role of Autophagy in Cisplatin Resistance in Ovarian Cancer Cells

Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blocking autophagy

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