Abstract 3588: Androgen synthesis disruption, ferroptosis induction and prostate cancer inhibition by androgen and vitamin D combination
Authors: Bobae Park, Jacqueline Vaquiz, Okunola Igbekoyi, Bandana Chatterjee
Journal: Cancer Research (2024)

Abstract Background: Metastatic castration-resistant prostate cancer (CRPC) is a fatal condition that progresses to end-of-life within two years, and it is the fifth leading cause of cancer death in men globally. New avenues for preventing or delaying lethal CRPC progression are a critical unmet need. Hormonal vitamin D3 (calcitriol) inhibits prostate cancer - both castration sensitive and castration resistant - in preclinical models, as documented widely. However, vitamin D as an anti-cancer therapeutic is clinically untenable since prostate tumor suppression in patients requires hormone dosing at a supraphysiologic level which induces hypercalcemia and other toxicities. Results: Herein we provide the first evidence that a subnanomolar, non-calcemic calcitriol dose can inhibit CRPC cell proliferation, G1 to S phase transition, clonal growth, migration, and invasion in vitro, and xenograft growth in vivo, only upon concurrent dosing with 5α-DHT at a physiologic or subphysiologic level. Calcitriol as a single treatment is non-inhibitory at a subnanomolar dose. HSD3β1, a hydroxysteroid dehydrogenase, was markedly induced by calcitriol, while DHT cotreatment reduced the induction. HSD3β1 catalyzes conversion of dehydroepiandrosterone, an adrenal androgen, to androstenedione (AED) - a rate-limiting step in the androgen biosynthesis pathway. AKR1C3, an aldo-keto reductase which promotes androgen biosynthesis, was also reduced by calcitriol/DHT cotreatment. In contrast, AKR1D1, an androgen-inactivating 5β-reductase, was robustly induced by a non-calcemic calcitriol dose in the presence of DHT, not by calcitriol singly. AKR1D1 converts AED and testosterone to 5β-diols. HSD3β1 and AKR1C3 are elevated in CRPC. Disruption of androgen biosynthesis and net reduction of the intratumor androgen pool are expected outcomes of reduced HSD3β1 and AKR1C3, and elevated AKR1D1. The hormone pair led to LC3B induction, ferritin degradation, and induction of ALOX-5 and NCoA4 - the genes which regulate ferroptosis, indicating autophagy mediated ferroptosis (ferritinophagy). Apoptosis and necroptosis were absent. We conclude that vulnerabilities created by combined androgen and non-calcemic vitamin D dosing can lead to cell death by ferroptosis, and this hormone pairing may be a new avenue for arresting CRPC clinical progression. Significance: The translational potential of our results is bolstered by the precedent that supraphysiologic testosterone improved serum PSA scores and other clinical parameters for a subset of therapy-inert CRPC patients who received repeated cycles of once-a-month single testosterone dosing- a protocol known as bipolar androgen therapy (BAT)1. Our findings may offer a strategic framework for enhancing the efficacy of BAT by including oral dosing of a non-calcemic level of vitamin D3. W81XWH-21-1-0307 (DoD); IK6 BX004207 (VA). Ref 1: Nat Rev Urol 2023; PMID 36543976 Citation Format: Bobae Park, Jacqueline Vaquiz, Okunola Igbekoyi, Bandana Chatterjee. Androgen synthesis disruption, ferroptosis induction and prostate cancer inhibition by androgen and vitamin D combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3588.