SQSTM1/p62 loss reverses the inhibitory effect of sunitinib on autophagy independent of AMPK signaling

Bolin Hou, Gang Wang, Quan Gao, Yanjie Wei, Caining Zhang, Yange Wang, Yuqing Huo, Huaiyi Yang, Xuejun Jiang, Zhijun Xi

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Abstract

Sunitinib (ST), a multitargeted receptor tyrosine kinase inhibitor, has been demonstrated to be effective for the treatment of renal carcinoma. It has been reported that ST is involved in the mediation of autophagy; however, its regulatory role in the autophagic process remains controversial. Furthermore, the mechanism by which activated AMP-activated protein kinase (AMPK) negatively regulates autophagy remains nearly unexplored. In the present study, we revealed that ST inhibited AMPK activity and regulated autophagy in a cell type- and dose-dependent manner. In a number of cell lines, ST was demonstrated to inhibit H2O2-induced autophagy and the phosphorylation of acetyl-CoA carboxylase (ACC), whereas alone it could block the autophagic flux concurrent with increased expression of p62. An immunoprecipitation assay revealed that LC3 directly interacted with p62, whereas ST increased punctate LC3 staining, which was well colocalized with p62. Taken together, we reveal a previously unnoticed pathway for ST to regulate the autophagic process, and p62, although often utilized as a substrate in autophagy, plays a critical role in regulating the inhibition of ST in both basal and induced autophagy.

Original languageEnglish (US)
Article number11087
Number of pages1
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Jul 31 2019

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    Hou, B., Wang, G., Gao, Q., Wei, Y., Zhang, C., Wang, Y., Huo, Y., Yang, H., Jiang, X., & Xi, Z. (2019). SQSTM1/p62 loss reverses the inhibitory effect of sunitinib on autophagy independent of AMPK signaling. Scientific reports, 9(1), [11087]. https://doi.org/10.1038/s41598-019-47597-4