Ubenimex attenuates acquired sorafenib resistance in renal cell carcinoma by inhibiting Akt signaling in a lipophagy associated mechanism.
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.
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
Shuai
S
Liu
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
Mingwei
M
Gao
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
Xiaoqing
X
Wang
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
Sentai
S
Ding
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
Jiaju
J
Lv
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
Dexuan
D
Gao
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
Zhiyang
Z
Wang
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
Zhihong
Z
Niu
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
D010671:Phenylurea Compounds; D009536:Niacinamide; C025946:3-methyladenine; D000077157:Sorafenib; D051057:Proto-Oncogene Proteins c-akt; D007930:Leucine; C012211:ubenimex; D000225:Adenine
Akt pathway; lipophagy; renal cell carcinoma; sorafenib resistance; ubenimex