Liao Liqiong, Zhang Zhixiong, Li Zhenhua, Wei Daqiang, Xie Yanni, Zeng Haodong, Zhao Hongyang, Zhou Yuhao, Gu Di, Duan Xiaolu
Guangdong Provincial Key Laboratory of Urological Diseases, Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Urology, Guangzhou, China.
Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Mol Carcinog. 2025 Oct;64(10):1778-1791. doi: 10.1002/mc.70023. Epub 2025 Aug 12.
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.
丝氨酸棕榈酰转移酶长链-1（SPTLC1）是神经酰胺合成中的关键酶，先前被鉴定为透明细胞肾细胞癌（ccRCC）肿瘤发生的抑制因子。尽管超长链神经酰胺水平升高与ccRCC中的经典多药耐药相关，但SPTLC1在调节ccRCC对舒尼替尼敏感性方面的具体作用仍不清楚。在本研究中，我们发现SPTLC1过表达可通过下调CerS2表达和长链神经酰胺水平来增强786-O和OSRC-2细胞对舒尼替尼的敏感性。相反，SPTLC1上调了A498细胞中CerS2的表达和长链神经酰胺水平，但对其对舒尼替尼的敏感性没有显著影响。此外，CerS2的过表达显著减弱了SPTLC1增强的786-O和OSRC-2细胞对舒尼替尼的敏感性，而敲低CerS2则明显增强了A498细胞对舒尼替尼的敏感性。此外，在SPTLC1过表达的786-O细胞中雄激素受体（AR）表达显著降低，强制表达AR可明显减弱SPTLC1诱导的786-O细胞中CerS2表达的下调，而在A498细胞中观察到相反的结果，这表明SPTLC1对CerS2表达的矛盾作用是由AR调节的。综上所述，我们的结果表明，SPTLC1对透明细胞肾细胞癌对舒尼替尼敏感性的矛盾作用是由AR介导的CerS2表达引起的，从而揭示了SPTLC1在调节ccRCC对舒尼替尼敏感性方面的新作用和机制。
