Ubenimex attenuates acquired sorafenib resistance in renal cell carcinoma by inhibiting Akt signaling in a lipophagy associated mechanism
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Shuai Liu1, Mingwei Gao1, Xiaoqing Wang1, Sentai Ding1, Jiaju Lv1, Dexuan Gao1, Zhiyang Wang1, Zhihong Niu1
1Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China
Zhihong Niu, email: email@example.com
Keywords: renal cell carcinoma, sorafenib resistance, lipophagy, Akt pathway, ubenimex
Received: April 23, 2016 Accepted: October 26, 2016 Published: November 01, 2016
Sorafenib is used as first line treatment of renal cell carcinoma (RCC) due to the poor sensitivity to radiotherapy and chemotherapy of this malignancy; however, acquired resistance limits the application of sorafenib and its analogues. In this study, we explored a new strategy to overcome acquired resistance to sorafenib. The RCC cell lines 786-O and ACHN were cultured in presence of increasing concentrations of sorafenib to generate sorafenib-resistant cell lines, 786-O-R and ACHN-R. Interestingly, treatment with ubenimex (0.25 mg/ml) and 3-MA (2 mM) restored the sensitivity of resistant cell lines to sorafenib, indicating the involvement of autophagy in acquired resistance. High levels of autophagy flux were observed in resistant cells, and the opposite effects of ubenimex and 3-MA suggested a complex role for autophagy. While 3-MA abolished protection in sorafenib-resistant cells, ubenimex induced uncontrolled autophagy and autophagic cell death. Lipophagy, characterized by a lipid droplet cargo, was observed in RCC tissues and cells. In sorafenib-resistant cells, ubenimex inhibited the Akt signaling pathway that regulates autophagy. In summary, lipophagy participates in sorafenib-resistance of RCC, which could be reversed by interventions targeting the Akt pathway.
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