Overexpression of ULK1 Represents a Potential Diagnostic Marker for Clear Cell Renal Carcinoma and the Antitumor Effects of SBI-0206965Research in context

Abstract

Background: Uncoordinated 51-like kinase 1 (ULK1) plays a vital role in autophagy. ULK1 dysregulation has recently been found in several human cancers. Methods: mRNA expression levels of ULK1 and clinical information were analysed from The Cancer Genome Atlas data. ULK1 expression levels were verified in 36 paired fresh ccRCC tissue specimens by western blot analysis. Expression of ULK1 was knockdown by shRNA lentivirus. ULK1 activity was inhibited by SBI-0206965. The effect of inhibition of ULK1 was measured by detecting the apoptotic rate, autophagy, and the ratio of ROS and NADPH. The efficacy of SBI-0206965 in vivo was assessed by the murine xenograft model. Findings: ULK1 mRNA expression was significantly upregulated in clear cell renal cell carcinoma (ccRCC) and overexpression of ULK1 correlated with poor outcomes. We found that ULK1 was highly expressed in 66.7% of ccRCC tumours (p < 0·05). Knockdown of ULK1 and selective inhibition of ULK1 by SBI-0206965 induced cell apoptosis in ccRCC cells. We demonstrated that SBI-0206965 triggered apoptosis by preventing autophagy and pentose phosphate pathway (PPP) flux. Furthermore, blocking the kinase activity of ULK1 with SBI-0206965 resulted in a level of anticancer effect in vivo. Interpretation: Taken together, our results suggested that ULK1 was upregulated in ccRCC tumours and may be a potential therapeutic target. Therefore, SBI-0206965 should be further considered as an anti-ccRCC agent. Fund: This work was supported in part by The National Natural Science Foundation of China (No. 81570748) and Natural Science Foundation of Fujian Province (No. 2018J01345, 2017XQ1194). Keywords: Clear cell renal carcinoma (ccRCC), SBI-0206965, ULK1