Macroautophagy and ERK phosphorylation counteract the anti-proliferative effect of proteasome inhibitor in gastric cancer cells

Wu, William; Cho, Chi Hin; Lee, Chung Wa; Wu, Yuzhong; Yu, Le; Li, Zhi Jie; Wong, Clover Ching Man; Li, Hai Tao; Zhang, Lin; Ren, Shun X.; Tao, Chun; Wu, Kaichun; Fan, Daiming; Yu, Jin; Sung, Joseph J.Y.

doi:10.4161/auto.6.2.11042

Cited by 42 publications

(37 citation statements)

References 47 publications

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“…On the contrary, in the thyroid cancer cell line FRO82-1 bortezomib, as well as epoxomicin, increased the expression of LC3-II protein but reduced the protein level of Beclin-1 [78]. Another proteasome inhibitor MG-132, in a time-and dose-dependent manner increased the content of LC3-II in HCT116 cells [75], colon cancer cells HT-29 [79,80] and SW1116 [80], thyroid cancer cells [78], gastric cancer cells [81], HeLa cells [82], prostate cancer DU145 cells and MEFs [75] and in immortalized dopaminergic neuronal N27 cell line [83]. In the majority of the above-mentioned experimental conditions there were no significant changes in Beclin-1 levels, and in thyroid cancer cells a decrease of Beclin-1 protein level has been reported [78].…”

Section: Effects Of Different Classes Of Proteasome Inhibitors On Autmentioning

confidence: 99%

“…Inhibited mTORC1 disinhibits kinase Ulk1/2 activities, resulting in FIP200 phosphorylation, which is required for the early stages of autophagosome formation [50]. It has been reported that after MG-132 application in various experimental cell culture models [79][80][81]121] characteristic features of increased autophagy were accompanied by pronounced inhibition of mTORC1-mediated phosphorylation of 4E-BP1 and S6K. Initially, the mechanism by which proteasome inhibition resulted in the disruption of mTORC1 remained vague, but recent studies using bortezomib as an autophagy inducer showing up-regulation of sestrin-2 (SESN2/Hi95) [122] have shed new light on this problem.…”

Section: Pi3k/akt/mtormentioning

confidence: 99%

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Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

Wójcik

2014

Folia Histochem Cytobiol.

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Abstract:The Ubiquitin-Proteasomes System (UPS) and autophagy, two main intracellular protein degradation pathways within the eukaryotic cells which were originally regarded as rather independent, seem to be very closely related. Proteasome inhibitors, including the multipathway inhibitor bortezomib, are drawing increased attention for their therapeutic potential in the treatment of chronic inflammation and cancer, especially tumours with a high degree of malignancy. The over-activation of autophagy induces cell death and may act as a powerful tumour-suppressing mechanism. However, autophagy, serving as an important mechanism to generate nutrients in time of cellular stresses, may directly contribute to the survival of cells treated with proteasome inhibitors, and in consequence, may decrease the effectiveness of therapy. Results of studies performed on several cancer cell lines demonstrated synergy between proteasome inhibitors and autophagy inhibitors. Those results became the base for ongoing clinical trials investigating autophagy inhibition in combination with anti-cancer therapies, including bortezomib. This review provides summary of the latest data on the functioning of the UPS and the mechanisms of autophagy. The new insights describing the main pathways of autophagy activation in response to UPS inhibition related to: (i) Unfolded Protein Response, (ii) PI3K/Akt/mTOR pathway, and (iii) formation of aggresomes, are discussed. It is concluded that concomitant inhibition of the two main cellular protein degradation systems may provide new therapeutic modalities for cancer treatment.

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Section: Effects Of Different Classes Of Proteasome Inhibitors On Autmentioning

confidence: 99%

Section: Pi3k/akt/mtormentioning

confidence: 99%

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

Wójcik

2014

Folia Histochem Cytobiol.

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“…15 When proteasomal degradation is either overwhelmed or inhibited, misfolded and ubiquitinated proteins that accumulate in the cytosol are transported to perinuclear aggresomes, which then are sequestered within autophagosomes that subsequently fuse with lysosomes for degradation of their contents. [16][17][18] Simultaneous proteasome and autophagy inhibition therefore leads to accumulation of ubiquitinated proteins and synergistic cytotoxicity in preclinical models. 19,20 Hydroxychloroquine (HCQ), a drug with a favorable and well-defined toxicity profile that is commonly used to treat autoimmune diseases, is a known inhibitor of autophagy.…”

Section: Combined Autophagy and Proteasome Inhibitionmentioning

confidence: 99%

Combined autophagy and proteasome inhibition

et al. 2014

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“…Autophagy is induced by different forms of cancer therapy, including conventional chemotherapeutic drugs, novel targeted cancer therapeutics and ionizing radiation, in various types of solid and hematological malignancies (Table 2) (Han et al, 2007(Han et al, , 2008Kim et al, 2007Kim et al, , 2008bKim et al, , 2009aMaiuri et al, 2007b;Kamitsuji et al, 2008;Meschini et al, 2008;Qadir et al, 2008;Turcotte et al, 2008;Fu et al, 2009;Lorin et al, 2009;Tormo et al, 2009;Fan et al, 2010;Gupta et al, 2010;Huang and Sinicrope, 2010;Li and Fan, 2010;Voss et al, 2010;Yacoub et al, 2010;Wu et al, 2010c;Lian et al, 2011;O'Donovan et al, 2011). In some circumstances, autophagy mediates the cytotoxic or cytostatic effect of anticancer agents, in which blockade of autophagy abolishes the therapeutic actions.…”

Section: Autophagy and Its Outcome Determinants In Cancer Therapymentioning

confidence: 99%

The autophagic paradox in cancer therapy

et al. 2011

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Autophagy, hallmarked by the formation of doublemembrane bound organelles known as autophagosomes, is a lysosome-dependent pathway for protein degradation. The role of autophagy in carcinogenesis is context dependent. As a tumor-suppressing mechanism in earlystage carcinogenesis, autophagy inhibits inflammation and promotes genomic stability. Moreover, disruption of autophagy-related genes accelerates tumorigenesis in animals. However, autophagy may also act as a prosurvival mechanism to protect cancer cells from various forms of cellular stress. In cancer therapy, adaptive autophagy in cancer cells sustains tumor growth and survival in face of the toxicity of cancer therapy. To this end, inhibition of autophagy may sensitize cancer cells to chemotherapeutic agents and ionizing radiation. Nevertheless, in certain circumstances, autophagy mediates the therapeutic effects of some anticancer agents. Data from recent studies are beginning to unveil the apparently paradoxical nature of autophagy as a cellfate decision machinery. Taken together, modulation of autophagy is a novel approach for enhancing the efficacy of existing cancer therapy, but its Janus-faced nature may complicate the clinical development of autophagy modulators as anticancer therapeutics.

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Macroautophagy and ERK phosphorylation counteract the anti-proliferative effect of proteasome inhibitor in gastric cancer cells

Abstract: Sung (2010) Macroautophagy and ERK phosphorylation counteract the anti-proliferative effect of proteasome inhibitor in gastric cancer cells, Autophagy, 6:2, 228-238,

Cited by 42 publications

References 47 publications

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

Combined autophagy and proteasome inhibition

The autophagic paradox in cancer therapy

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