Abstract
Background
Autophagy can function in a dual role in cancer development and progression: It can be cytoprotective or contribute to cell death. Therefore, determining the contextual role of autophagy between these two opposing effects is important. So far, little is known about the role of autophagy in uveal melanoma. In the present study, we looked to investigate the autophagic process, as well as its effect on cell survival in uveal melanoma cell lines under stressed conditions (starvation). The possible role of autophagy during BRAF inhibition in uveal melanoma was also sought.
Methods
Two human uveal melanoma cell lines, OCM1A, which harbors the BRAF mutation V600E and Mel 290, which is BRAF wild type, were studied. Autophagy levels were determined by Western blot assay with/without the addition of autophagic flux inhibitor (bafilomycin A1). Cell proliferation was assessed by an MTT assay.
Results
Starvation triggered autophagy in BRAF V600E-mutant OCM1A cells but not in BRAF wild-type Mel 290 cells. Enhanced autophagy helped the OCM1A cells survive under stressed conditions. The BRAF inhibitor vemurafenib upregulated autophagy through suppression of the PI3K/Akt/mTOR/p70S6 K pathway in BRAF V600E-mutant uveal melanoma cells. Autophagy inhibition impaired the treatment efficacy of vemurafenib in BRAF V600E-mutant uveal melanoma cells.
Conclusions
Our data demonstrate that starvation-trigged autophagy, which is BRAF V600E dependent, promotes cancer cell survival in uveal melanoma. Vemurafenib induces autophagic cell death rather than adaptive cell survival in BRAF V600E-mutant melanoma.
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Acknowledgements
This study is partially supported by the Dancer’s Care Foundation, Grants from the National Natural Science Foundation of China (No. 81202141), scholarship from China Scholarship Council (CSC, No. 201308330175), the Key Project of Scientific and Technological Innovation of Zhejiang Province (No. 2015C03G2010206). The authors thank Dr. Gary K. Schwartz (Columbia University Medical Center) for providing cells.
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Yinu Zhao and Weibin Wang have contributed equally to this study.
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Zhao, Y., Wang, W., Min, I. et al. BRAF V600E-dependent role of autophagy in uveal melanoma. J Cancer Res Clin Oncol 143, 447–455 (2017). https://doi.org/10.1007/s00432-016-2317-y
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DOI: https://doi.org/10.1007/s00432-016-2317-y