The Contradictory Effects of SPTLC1 on Clear Cell Renal Carcinoma Sensitivity to Sunitinib Mediated by Androgen Receptor

ABSTRACT Serine palmitoyltransferase long chain‐1 (SPTLC1) is a key enzyme in ceramide synthesis, previously identified as a suppressor of tumorigenesis in clear cell renal carcinoma (ccRCC). Although elevated levels of very long‐chain ceramides are associated with the canonical multidrug resistance in ccRCC, the specific role of SPTLC1 in modulating the sensitivity of ccRCC to sunitinib remains unclear. In this study, we found that SPTLC1 overexpression could enhance the sensitivities of 786‐O and OSRC‐2 cells to sunitinib via downregulating CerS2 expression and long‐chain ceramide levels. In contrast, SPTLC1 upregulated CerS2 expression and long‐chain ceramide levels in A498 cells, yet without a significant impact on its sensitivity to sunitinib. In addition, overexpression of CerS2 significantly attenuated SPTLC1‐enhanced sensitivities of 786‐O and OSRC‐2 cells to sunitinib, whereas CerS2 knockdown obviously enhanced the sensitivity of A498 cells to sunitinib. Moreover, androgen receptor (AR) expression was significantly decreased in SPTLC1‐overexpressed 786‐O cells and forced AR expression could obviously attenuate the downregulation of CerS2 expression induced by SPTLC1 in 786‐O cells, whereas opposite results were observed in A498 cells, suggesting that the contradictory effects of SPTLC1 on CerS2 expression were modulated by AR. Taken together, our results demonstrated that the contradictory effects of SPTLC1 on clear cell renal carcinoma sensitivity to sunitinib were caused by AR‐mediated CerS2 expression, thus revealing a novel role and mechanism of SPTLC1 in the regulation of ccRCC sensitivity to sunitinib.