Sprouty2 loss‐induced IL 6 drives castration‐resistant prostate cancer through scavenger receptor B1

Abstract

Metastatic castration‐resistant prostate cancer (mCRPC) is a lethal form of treatment‐resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre‐clinical human and murine mCRPC models, we show that SPRY2 deficiency leads to an androgen self‐sufficient form of CRPC. Mechanistically, HER2‐IL6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD3B1 and increases SRB1‐mediated cholesterol uptake in SPRY2‐deficient tumours. Systemically, IL6 elevated the levels of circulating cholesterol by inducing host adipose lipolysis and hepatic cholesterol biosynthesis. SPRY2‐deficient CRPC is dependent on cholesterol bioavailability and SRB1‐mediated tumoral cholesterol uptake for androgen biosynthesis. Importantly, treatment with ITX5061, a clinically safe SRB1 antagonist, decreased treatment resistance. Our results indicate that cholesterol transport blockade may be effective against SPRY2‐deficient CRPC.

Leukemia Inhibitory Factor Promotes Castration-resistant Prostate Cancer and Neuroendocrine Differentiation by Activated ZBTB46

“…Although we demonstrated that LIF is a direct target of ZBTB46, our results show that an increase in LIF protein can also induce ZBTB46, suggesting a positive feedback loop between ZBTB46 and LIF-STAT3 signaling. In addition to the involvement of the IL6 cytokine axis in prostate cancer resistance to AR antagonists (43,44), we showed that targeting AR activity induces both ZBTB46 and LIF; it is possible that factors downstream of STAT3 signaling are involved in the androgen resistance phenotype, partly through induction of ZBTB46. Because of the oncogenic function of ZBTB46 observed in prostate cancer cells (24), the induction of LIF expression by suppression of AR signaling would provide a selective advantage to cells that stimulate STAT3 signaling during CRPC-NE progression.…”

Lipid Uptake Is an Androgen-Enhanced Lipid Supply Pathway Associated with Prostate Cancer Disease Progression and Bone Metastasis

“…Hypercholesterolemia has been reported to enhance LNCaP tumor xenograft growth and intratumoral androgen synthesis (69), and monotherapy against dietary cholesterol adsorption in the intestine with ezetimibe (67) or de novo cholesterol synthesis with simvastatin (66) reduced LNCaP tumor xenograft growth, androgen steroidogenesis, and delayed development of CRPC. Furthermore, targeting cholesterol uptake via SCARB1 antagonism with ITX5061 reduced HDL uptake (but not LDL) in LNCaP, VCaP, and CRW22Rv1 cells and sensitized CWR22Rv1 tumor orthografts to ADT (68). Comparatively, the same study showed that ITX5061 conferred stronger growth inhibition than simvastatin in LNCaP and CWR22Rv1 cells (68) under hormone-deprived conditions, suggesting that cholesterol uptake via SCARB1 is a significant supply route in this prostate cancer model.…”

“…Targeting cholesterol homeostasis in prostate cancer as a therapeutic strategy to delay development of CRPC has recently received increasing attention (66)(67)(68). Cholesterol is a precursor of steroid hormone synthesis, and we previously showed that progression to CRPC is associated with increased intratumoral steroidogenesis of androgens (34).…”

Bright insights into palladium-triggered local chemotherapy

“…Given the medical interest of our team in developing improved prostate cancer treatments, a state-of-the-art orthotopic murine model of human prostate cancer 45 , 46 was used to test the in vivo biocompatibility and functional stability of the Pd-devices. DU145 prostate cancer cells were carefully inserted in the prostate of anesthetized male mice ( n = 4) and tumours allowed to grow for 4 weeks (see full details in the ESI † ).…”