Oncotarget

Research Papers:

Ubenimex attenuates acquired sorafenib resistance in renal cell carcinoma by inhibiting Akt signaling in a lipophagy associated mechanism

Shuai Liu, Mingwei Gao, Xiaoqing Wang, Sentai Ding, Jiaju Lv, Dexuan Gao, Zhiyang Wang and Zhihong Niu _

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Oncotarget. 2016; 7:79141-79153. https://doi.org/10.18632/oncotarget.13003

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Abstract

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

Correspondence to:

Zhihong Niu, email: nzh1789@163.com

Keywords: renal cell carcinoma, sorafenib resistance, lipophagy, Akt pathway, ubenimex

Received: April 23, 2016     Accepted: October 26, 2016     Published: November 01, 2016

ABSTRACT

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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