Activation of a c-Jun N-terminal kinase-mediated autophagy pathway attenuates the anticancer activity of gemcitabine in human bladder cancer cells

Huang, Xiaolong; Zhang, Hao; Yang, Xiaoyu; Dong, Xiaoyong; Xie, X. Sunney; Yin, Hubin; Gou, Xin; Lin, Yong; He, Weiyang

doi:10.1097/cad.0000000000000499

Cited by 20 publications

(19 citation statements)

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“…In the present study, similarly to previous studies (6,18,33), it was observed that autophagy was activated when bladder cancer cells were exposed to hypoxia, as well as to gemcitabine. Notably, autophagy was enhanced when the cells were exposed to hypoxia and gemcitabine simultaneously, including increased GFP-LC3 puncta, enhanced formation of autophagic vacuoles and upregulation of LC3-II levels.…”

Section: Discussionsupporting

confidence: 90%

“…Chemotherapy is a beneficial treatment for prolonging the survival time of patients at an advanced tumor stage. Gemcitabine, a cytosine analogue that inhibits DNA synthesis, has been widely used to treat bladder cancer, and gemcitabine in combination with other chemotherapeutic drugs has become the preferred standard treatment for advanced urothelial carcinoma (4)(5)(6). However, drug resistance leads to treatment failure in bladder cancer.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation

et al. 2018

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Overcoming the chemoresistance of bladder cancer is a pivotal obstacle in clinical treatments. Hypoxia widely exists in solid tumors and has been demonstrated to contribute to chemoresistance through hypoxia-inducible factor 1α (HIF‑1α)-mediated autophagy in several types of cancer. However, it is unclear whether HIF‑1α-mediated autophagy and chemoresistance occur in bladder cancer. The present study demonstrated that HIF‑1α was overexpressed in 20 bladder cancer tissues compared with matched paracarcinoma tissues. Gemcitabine-induced apoptosis during hypoxia was significantly reduced compared with that observed under normoxic conditions. In addition, hypoxia activated autophagy and enhanced gemcitabine-induced autophagy. Combined treatment using gemcitabine and an autophagy inhibitor (3-methyladenine) under hypoxia significantly increased gemcitabine cytotoxicity. Furthermore, it was demonstrated that hypoxia-activated autophagy depended on the HIF‑1α/BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)/Beclin1 signaling pathway. Suppressing HIF‑1α inhibited autophagy, BNIP3 and Beclin1, as well as enhanced gemcitabine-induced apoptosis in bladder cancer cells under hypoxic conditions. Consequently, the results of the present study demonstrated that hypoxia-induced cytoprotective autophagy counteracted gemcitabine-induced apoptosis through increasing HIF‑1α expression. Therefore, targeting HIF‑1α-associated pathways or autophagy in bladder cancer may be a successful strategy to enhance the sensitivity of bladder cancer chemotherapy.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation

et al. 2018

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“…The role of JNK in promoting cancer cell survival involves autophagy, as JNK can induce autophagy to counteract apoptosis . Extensive evidence supports that JNK‐mediated prosurvival autophagy promotes cancer cell resistance to chemotherapy, and recent studies suggest the involvement of tumor immune evasion in this process . JNK is closely related to traditional regulatory factors of immune evasion such as transforming growth factor‐β (TGF‐β) and interferon‐γ (IFN‐γ) .…”

Section: Introductionmentioning

confidence: 99%

JNK signaling in cancer cell survival

et al. 2019

Medicinal Research Reviews

205

146

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c‐Jun N‐terminal kinase (JNK) is involved in cancer cell apoptosis; however, emerging evidence indicates that this Janus signaling promotes cancer cell survival. JNK acts synergistically with NF‐κB, JAK/STAT, and other signaling molecules to exert a survival function. JNK positively regulates autophagy to counteract apoptosis, and its effect on autophagy is related to the development of chemotherapeutic resistance. The prosurvival effect of JNK may involve an immune evasion mechanism mediated by transforming growth factor‐β, toll‐like receptors, interferon‐γ, and autophagy, as well as compensatory JNK‐dependent cell proliferation. The present review focuses on recent advances in understanding the prosurvival function of JNK and its role in tumor development and chemoresistance, including a comprehensive analysis of the molecular mechanisms underlying JNK‐mediated cancer cell survival. There is a focus on the specific “Yin and Yang” functions of JNK1 and JNK2 in the regulation of cancer cell survival. We highlight recent advances in our knowledge of the roles of JNK in cancer cell survival, which may provide insight into the distinct functions of JNK in cancer and its potential for cancer therapy.

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“… 7 The JNK pathway plays an important role as a classical signaling pathway in the regulation of tumor cell apoptosis and autophagic death. 8 The function of JNK as a regulator in apoptosis and autophagic cell death has been demonstrated in many tumor cells, such as bladder tumor, osteosarcoma, breast cancer, and hepatocellular carcinoma. 8 – 11 In melanoma, JNK also plays a vital role in proliferation and cell death.…”

Section: Introductionmentioning

confidence: 99%

“… 8 The function of JNK as a regulator in apoptosis and autophagic cell death has been demonstrated in many tumor cells, such as bladder tumor, osteosarcoma, breast cancer, and hepatocellular carcinoma. 8 – 11 In melanoma, JNK also plays a vital role in proliferation and cell death. 12 The Akt pathway is often regulated in response to DNA-damaging chemotherapeutics, and participates in regulating tumor cell death.…”

Section: Introductionmentioning

confidence: 99%

Role of ubenimex as an anticancer drug and its synergistic effect with Akt inhibitor in human A375 and A2058 cells

Wang

Liu

et al. 2018

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BackgroundMalignant melanoma (MM) is a malignant tumor produced by changes in melanocytes in the skin or other organs. In the classification of skin tumor mortality, skin melanoma ranks the highest. Ubenimex, an Aminopeptidase N (APN) inhibitor, is now widely used for cancer as an adjunct therapy, conferring antitumor effects. Apoptosis and the induction of autophagy have both been found to be closely associated with tumor cell death.MethodsIn this study, the A375 and A2058 cell lines were treated with ubenimex. Cell viability was measured using the Cell Counting Kit 8 assay. Apoptosis and autophagic cell death were assessed using flow cytometry and acridine orange/ethidium bromide staining. Protein expression was assessed by Western blot analyses and immunofluorescence. Matrigel invasion and migration assays were used to examine the metastatic ability of melanoma cells.ResultsThe results revealed that ubenimex inhibited the expression of APN in melanoma cells, which may be connected with the inhibition of metastasis. In addition, it increased melanoma cell death by inducing apoptosis and autophagic cell death. This effect was accompanied by increased levels of p-JNK. Moreover, treatment with ubenimex induced protective Akt activation, and combined use of an Akt inhibitor with ubenimex provided a better effect for inducing tumor cell death.ConclusionAs an effective anti-tumor drug in vitro, ubenimex might be an excellent adjunctive therapy for the treatment of melanoma, with greater effects when combined with the use of an Akt inhibitor.

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Activation of a c-Jun N-terminal kinase-mediated autophagy pathway attenuates the anticancer activity of gemcitabine in human bladder cancer cells

Cited by 20 publications

References 25 publications

Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation

Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation

JNK signaling in cancer cell survival

Role of ubenimex as an anticancer drug and its synergistic effect with Akt inhibitor in human A375 and A2058 cells

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