Role of Autophagy in Cisplatin Resistance in Ovarian Cancer Cells

Wang, Juan; Wu, Gen Sheng

doi:10.1074/jbc.m114.558288

Cited by 244 publications

(194 citation statements)

References 47 publications

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“…Wang et al demonstrated that cisplatininduced autophagy is regulated by the ERK pathway, which is in turn associated with the Atg5 pathway (Wang and Wu, 2014). In our results, treatment with SSZ induced activation of ERK pathway ( Figure 7) and increased Atg5-12 complex ( Figure 5) respectively.…”

Section: Lc3-i Lc3-iisupporting

confidence: 66%

Sulfasalazine Induces Autophagic Cell Death in Oral Cancer Cells via Akt and ERK Pathways

Han¹,

Kim²,

Jeong³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Sulfasalazine (SSZ) is an anti-inflammatory drug that has been used to treat inflammatory bowel disease and rheumatoid arthritis for decades. Recently, some reports have suggested that SSZ also has anti-cancer properties against human tumors. However, little is known about the effects of SSZ on oral cancer. The aim of this study was to investigate the anti-cancer effects of SSZ in oral squamous cell carcinoma (OSCC) cells and to elucidate the mechanisms involved. The authors investigated the anti-proliferative effect of SSZ using the MTT method in HSC-4 cells (an OSCC cell line). Cell cycle analysis, acidic vesicular organelle (AVO) staining, monodansylcadaverine (MDC) staining and Western blotting were also conducted to investigate the cytotoxic mechanism of SSZ. SSZ significantly inhibited the proliferation of HSC-4 cells in a dose-dependent manner. In addition, SSZ induced autophagic cell death, increased microtubule-associated protein 1 light chain (MAP1-LC; also known as LC) 3-II levels, as well as induced punctate AVO and MDC staining, resulted in autophagic cell death. Furthermore, these observations were accompanied by the inhibition of the Akt pathway and the activation of ERK pathway. These results suggest that SSZ promotes autophagic cell death via Akt and ERK pathways and has chemotherapeutic potential for the treatment of oral cancer.

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Section: Lc3-i Lc3-iisupporting

confidence: 66%

Sulfasalazine Induces Autophagic Cell Death in Oral Cancer Cells via Akt and ERK Pathways

Han¹,

Kim²,

Jeong³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…Furthermore, PEBP1 did not affect MAPK/ERK activation following the treatment with cisplatin, an anticancer drug that generally activates the MAPK/ERK pathway to stimulate cell death in cancer cells and induces autophagy under certain conditions. [65][66][67] However, PEBP1 overexpression in HeLa cells significantly suppressed LC3-II, suggesting that PEBP1-dependent inhibition of autophagy does not require MAPK/ERK activity. These results were also observed in H1299 cells.…”

Section: Discussionmentioning

confidence: 99%

PEBP1, a RAF kinase inhibitory protein, negatively regulates starvation-induced autophagy by direct interaction with LC3

et al. 2016

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Autophagy plays a critical role in maintaining cell homeostasis in response to various stressors through protein conjugation and activation of lysosome-dependent degradation. MAP1LC3B/LC3B (microtubuleassociated protein 1 light chain 3 b) is conjugated with phosphatidylethanolamine (PE) in the membranes and regulates initiation of autophagy through interaction with many autophagy-related proteins possessing an LC3-interacting region (LIR) motif, which is composed of 2 hydrophobic amino acids (tryptophan and leucine) separated by 2 non-conserved amino acids (WXXL). In this study, we identified a new putative LIR motif in PEBP1/RKIP (phosphatidylethanolamine binding protein 1) that was originally isolated as a PE-binding protein and also a cellular inhibitor of MAPK/ERK signaling. PEBP1 was specifically bound to PE-unconjugated LC3 in cells, and mutation (WXXL mutated to AXXA) of this LIR motif disrupted its interaction with LC3 proteins. Interestingly, overexpression of PEBP1 significantly inhibited starvationinduced autophagy by activating the AKT and MTORC1 (mechanistic target of rapamycin [serine/ threonine kinase] complex 1) signaling pathway and consequently suppressing the ULK1 (unc-51 like autophagy activating kinase 1) activity. In contrast, ablation of PEBP1 expression dramatically promoted the autophagic process under starvation conditions. Furthermore, PEBP1 lacking the LIR motif highly stimulated starvation-induced autophagy through the AKT-MTORC1-dependent pathway. PEBP1 phosphorylation at Ser153 caused dissociation of LC3 from the PEBP1-LC3 complex for autophagy induction. PEBP1-dependent suppression of autophagy was not associated with the MAPK pathway. These findings suggest that PEBP1 can act as a negative mediator in autophagy through stimulation of the AKT-MTORC1 pathway and direct interaction with LC3.

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“…However, acquired resistance to cisplatin remains a major limitation of its success clinically in ovarian cancer. Increasing evidence indicates that autophagy plays an important role in the prosurvival and resistance against chemotherapy, however, the underlying mechanisms have not been fully elucidated (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Silencing of BAG3 promotes the sensitivity of ovarian cancer cells to cisplatin via inhibition of autophagy

et al. 2017

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Abstract. Ovarian cancer is the most lethal disease among all gynecological malignancies. Interval cytoreductive surgery and cisplatin-based chemotherapy are the recommended therapeutic strategies. However, acquired resistance to cisplatin remains a big challenge for the overall survival and prognosis in ovarian cancer. Complicated molecular mechanisms are involved in the process. At present, increasing evidence indicates that autophagy plays an important role in the prosurvival and resistance against chemotherapy. In the present study, as a novel autophagy regulator, BCL2-associated athanogene 3 (BAG3) was investigated to study its role in cisplatin sensitivity in epithelial ovarian cancer. However, whether BAG3 participates in cisplatin sensitivity by inducing autophagy and the underlying mechanism in ovarian cancer cells remain to be clarified. Through the use of quantitative real-time PCR, western blot analysis, CCK-8 and immunofluorescence assays our data revealed that cisplatin-induced autophagy protected ovarian cancer cells from the toxicity of the drug and that this process was regulated by BAG3. Silencing of BAG3 increased cisplatininduced apoptosis. The results also revealed BAG3 as a potential therapeutic target which enhanced the efficacy of cisplatin in ovarian cancer.

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Role of Autophagy in Cisplatin Resistance in Ovarian Cancer Cells

Cited by 244 publications

References 47 publications

Sulfasalazine Induces Autophagic Cell Death in Oral Cancer Cells via Akt and ERK Pathways

Sulfasalazine Induces Autophagic Cell Death in Oral Cancer Cells via Akt and ERK Pathways

PEBP1, a RAF kinase inhibitory protein, negatively regulates starvation-induced autophagy by direct interaction with LC3

Silencing of BAG3 promotes the sensitivity of ovarian cancer cells to cisplatin via inhibition of autophagy

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