Xu Zhenzhou, Huang Liang, Dai Tao, Pei Xiaming, Xia Longzheng, Zeng Gongqian, Ye Mingji, Liu Kan, Zeng Fuhua, Han Weiqing, Jiang Shusuan
Department of Urology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, 410013, Hunan, People's Republic of China.
Onco Targets Ther. 2021 Jul 24;14:4285-4295. doi: 10.2147/OTT.S315813. eCollection 2021.
Almost all metastatic hormone-sensitive prostate cancers (mHSPC) will develop into metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT). The expression level of squalene monooxygenase (SQLE) is increased in CRPC cells and regulates cholesterol metabolism. This study verified the biological function and mechanisms of SQLE in CRPC.
The expression of SQLE in human prostate cancer cells was overexpressed or silenced and its efficacy on cell survival was determined by the MTS test. Energy metabolism phenotype test was evaluated by XF real-time ATP rate assay, XF cell mitochondrial stress test, XF glycolysis stress test and XF mito fuel flex test. Cell migration and invasion were evaluated by colony formation assays and transwell assays; the expression of mRNA and protein was assessed by RT-qPCR and Western blot, respectively. Moreover, BALB/c nude mice model was performed to evaluate the lymph node metastasis.
In our study, we found that the expression level of SQLE was significantly increased in bicalutamide-resistant-C4-2B cells compared to LNCaP cells. SQLE knockdown partly restored the sensitivity of drug-resistant cells to bicalutamide and reduced lymph node metastasis by inhibiting fatty acid oxidation in mitochondria. We also found that terbinafine, the specific inhibitor of SQLE, can enhance the sensitivity of prostate cancer cells to bicalutamide.
Our study revealed that SQLE is involved in the progression of castration resistance in CRPC through mediating metabolic reprogramming, presenting SQLE as a new target for the treatment of mCRPC.
几乎所有转移性激素敏感性前列腺癌（mHSPC）在雄激素剥夺治疗（ADT）后都会发展为转移性去势抵抗性前列腺癌（mCRPC）。角鲨烯单加氧酶（SQLE）在CRPC细胞中的表达水平升高，并调节胆固醇代谢。本研究验证了SQLE在CRPC中的生物学功能及机制。
在人前列腺癌细胞中过表达或沉默SQLE，通过MTS试验确定其对细胞存活的影响。通过XF实时ATP速率测定、XF细胞线粒体应激试验、XF糖酵解应激试验和XF线粒体燃料灵活性试验评估能量代谢表型。通过集落形成试验和Transwell试验评估细胞迁移和侵袭；分别通过RT-qPCR和蛋白质印迹法评估mRNA和蛋白质的表达。此外，构建BALB/c裸鼠模型评估淋巴结转移情况。
在我们的研究中，我们发现与LNCaP细胞相比，比卡鲁胺耐药的C4-2B细胞中SQLE的表达水平显著升高。敲低SQLE可部分恢复耐药细胞对比卡鲁胺的敏感性，并通过抑制线粒体中的脂肪酸氧化减少淋巴结转移。我们还发现，SQLE的特异性抑制剂特比萘芬可增强前列腺癌细胞对比卡鲁胺的敏感性。
我们的研究表明，SQLE通过介导代谢重编程参与CRPC去势抵抗的进展，提示SQLE可作为治疗mCRPC的新靶点。
