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

Abstract

Background: 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.

Identification of novel prognostic biomarkers for osteosarcoma: a bioinformatics analysis of differentially expressed genes in the mesenchymal stem cells from single-cell sequencing data set

“…High SQLE expression and gene amplification are associated with a poor prognosis in head and neck squamous cell carcinoma ( 39 ). SQLE was also shown to mediate metabolic reprogramming to promote metastasis in castration-resistant prostate cancer ( 40 ). To date, the role of SQLE has not been examined in OS.…”

Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

“…Notably, studies have demonstrated that both cholesterol biosynthesis and efflux are reprogrammed in mCRPC, which may be major contributors to tumor growth and lethal progression [6][7][8]. Indeed, elevated expression of cholesterol biosynthesis rate-limiting enzymes such as SQLE have been strongly correlated with poor outcome of PCa [7,9,10]. Low or loss of expression of key efflux proteins such as ABCA1 and metabolic enzymes such as CYP27A1 are also associated with the disease progression [6,11].…”

Osteoclasts directly influence castration-resistant prostate cancer cells

“…Cholesterol is a vital component in cell membranes and a precursor for steroid synthesis, including androgens. In prostate cancer, high cholesterol and cholesterol biosynthesis have been associated with for example progression [ 48 ], metastasis [ 49 ], and poor treatment response to taxanes [ 50 ]. Together with the downregulation of the cholesterol synthesis pathway by ostecoclasts in the present study, this would indicate a suppressive role of osteoclasts on aggressive features associated with cholesterol.…”