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Implication of SEMA3C-induced steroidogenesis in the progression of castration-resistant prostate cancer Yenki, Parvin

Abstract

Androgens i.e. testosterone (T) and dihydrotestosterone (DHT), have essential roles in the differentiation and growth of normal prostate cells, as well as in the progression of prostate cancer (PCa) cells. Androgen deprivation therapy (ADT) is an effective therapy for PCa patients, however, prostate tumor cells progress to a treatment-resistant stage known as castration-resistant prostate cancer (CRPC). It has been established that CRPC cells have an acquired ability to synthesize androgens to resist the systemic androgen depletion imposed by ADT. This autonomous steroidogenesis in tumor cells, known as intratumoral steroidogenesis, provides a sufficient androgen level for their survival and growth. Discovering the gene networks or signaling pathways capable of upregulating intratumoral steroidogenesis is a major challenge in PCa research. Our laboratory studies the potential role of Semaphorin 3C (SEMA3C) in CRPC progression. This secreted signaling protein has been implicated in multiple cancer types, including PCa. Our previous findings showed SEMA3C’s potent ability to trigger receptor tyrosine kinase (RTK) signaling pathways independent to cognate ligand-binding, SEMA3C’s increased expression in CRPC bone metastasis, and also SEMA3C’s capability to promote epithelial-to-mesenchymal transition and stem-like characteristics. In the present work, we investigated whether SEMA3C is able to affect steroidogenesis from various substrates in epithelial PCa cells, and also in prostatic stromal cells, both of which can contribute to the synthesis of androgenic steroids in the tumor microenvironment. Work presented here demonstrates that SEMA3C can support androgen maintenance in prostate tumor cells in an androgen-deprived environment, by iv downregulating genes in the DHT inactivation pathway that irreversibly terminates the signal of this androgen receptor (AR) ligand. In parallel, SEMA3C upregulates genes coding for enzymes involved in T and DHT synthesis from cholesterol (de novo synthesis) or from circulatory adrenal hormones such as dehydroepiandrosterone (DHEA) (defined as derivative synthesis). We also observed that SEMA3C can alter expression of lipogenic or cholesterogenic genes by influencing sterol regulatory element binding proteins (SREBP) transcriptional activity. Collectively, findings of this study show that SEMA3C’s ability to increase androgen synthesis can contribute to castration-resistant growth of PCa cells in androgen-depleted environments as observed in our CRPC progression model.

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Attribution-NonCommercial-NoDerivatives 4.0 International