OncoTargets and Therapy (Jul 2021)

SQLE Mediates Metabolic Reprogramming to Promote LN Metastasis in Castration-Resistant Prostate Cancer

  • Xu Z,
  • Huang L,
  • Dai T,
  • Pei X,
  • Xia L,
  • Zeng G,
  • Ye M,
  • Liu K,
  • Zeng F,
  • Han W,
  • Jiang S

Journal volume & issue
Vol. Volume 14
pp. 4285 – 4295

Abstract

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Zhenzhou Xu,* Liang Huang,* Tao Dai,* Xiaming Pei, Longzheng Xia, Gongqian Zeng, Mingji Ye, Kan Liu, Fuhua Zeng, Weiqing Han, Shusuan Jiang 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*These authors contributed equally to this workCorrespondence: Zhenzhou Xu; Shusuan JiangDepartment of Urology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, 283# Tongzipo Road, Yuelu District, Changsha, Hunan, 4100013, People’s Republic of ChinaTel +86 18874728621; +86 18608408523Fax +86 73189762270Email [email protected]; [email protected]: 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.Methods: 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.Results: 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.Conclusion: 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.Keywords: SQLE, bicalutamide, CRPC, ADT, lymph node metastasis

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