Intratumoral androgen biosynthesis associated with 3β-hydroxysteroid dehydrogenase 1 promotes resistance to radiotherapy in prostate cancer
Shinjini Ganguly, … , Nima Sharifi, Omar Y. Mian
Shinjini Ganguly, … , Nima Sharifi, Omar Y. Mian
Published November 15, 2023
Citation Information: J Clin Invest. 2023;133(22):e165718. https://doi.org/10.1172/JCI165718.
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Research Article Endocrinology

Intratumoral androgen biosynthesis associated with 3β-hydroxysteroid dehydrogenase 1 promotes resistance to radiotherapy in prostate cancer

Abstract

Half of all men with advanced prostate cancer (PCa) inherit at least 1 copy of an adrenal-permissive HSD3B1 (1245C) allele, which increases levels of 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) and promotes intracellular androgen biosynthesis. Germline inheritance of the adrenally permissive allele confers worse outcomes in men with advanced PCa. We investigated whether HSD3B1 (1245C) drives resistance to combined androgen deprivation and radiotherapy. Adrenally permissive 3βHSD1 enhanced resistance to radiotherapy in PCa cell lines and xenograft models engineered to mimic the human adrenal/gonadal axis during androgen deprivation. The allele-specific effects on radiosensitivity were dependent on availability of DHEA, the substrate for 3βHSD1. In lines expressing the HSD3B1 (1245C) allele, enhanced expression of DNA damage response (DDR) genes and more rapid DNA double-strand break (DSB) resolution were observed. A correlation between androgen receptor (AR) expression and increased DDR gene expression was confirmed in 680 radical prostatectomy specimens. Treatment with the nonsteroidal antiandrogen enzalutamide reversed the resistant phenotype of HSD3B1 (1245C) PCa in vitro and in vivo. In conclusion, 3βHSD1 promotes prostate cancer resistance to combined androgen deprivation and radiotherapy by upregulating DNA DSB repair. This work supports prospective validation of early combined androgen blockade for high-risk men harboring the HSD3B1 (1245C) allele.

Authors

Shinjini Ganguly, Zaeem Lone, Andrew Muskara, Jarrell Imamura, Aimalie Hardaway, Mona Patel, Mike Berk, Timothy D. Smile, Elai Davicioni, Kevin L. Stephans, Jay Ciezki, Christopher J. Weight, Shilpa Gupta, Chandana A. Reddy, Rahul D. Tendulkar, Abhishek A. Chakraborty, Eric A. Klein, Nima Sharifi, Omar Y. Mian

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Figure 5

Enza pretreatment restores radiosensitivity.

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Enza pretreatment restores radiosensitivity. (A) Clonogenic survival of ...
(A) Clonogenic survival of Enza-treated cells following 0, 4, and 8 Gy IR treatment. Data are represented as mean ± 95% CI of 3 technical replicates. (B) Representative bioluminescence images of LNCaP xenografts undergoing oral gavage with either vehicle or Enza. (C)Tumor volume changes over the experimental duration for shControl and shHSD3B1 xenografts after 8 Gy IR, with and without Enza (shControl; n = 8, shHSD3B1; n = 8, shControl+Enza; n = 6) for each 0 Gy and 8 Gy IR treatment arm. P values were calculated using Mann-Whitney U test for nonparametric data analysis. Data are represented as mean ± SEM. (D) Doubling time of vehicle-treated shControl and shHSD3B1 tumors compared with Enza-treated shControl LNCaP tumors. All data are represented as mean values ± 95% CI (P values were calculated using 1-way ANOVA with Bonferroni’s multiple-comparison test). (E) Kaplan-Meier curve depicting the time to meet tumor volume greater than 1.5 cc for LNCaP xenografts. P values were calculated using log-rank test between groups. (F) Representative bioluminescence images of LAPC4 xenografts undergoing oral gavage with either vehicle or Enza with or without IR (n = 6 for each experimental condition for each HSD3B1 genotype). (G) Changes in tumor volume of LAPC4 (EV, 1245A, and 1245C) xenografts after 0 Gy (left) and 8 Gy IR (right). P values were calculated using Mann-Whitney U test for nonparametric data analysis. Data are represented as mean ± SEM. (H) Tumor-doubling time of LAPC4 xenografts that had undergone 8 Gy IR treatment. All data are represented as mean values ± 95% CI (P values were calculated using 1-way ANOVA with Bonferroni’s multiple-comparison test). (I) Kaplan-Meier curve depicting the time to meet tumor volume greater than 1.5 cc for LAPC4 xenografts. P values were calculated using log-rank test between groups. (J) Phospho-γ H2A.X foci formation and resolution after 4 Gy IR with Enza treatment in LNCaP cells in vitro. All data are represented as mean values ± 95% CI (P values were calculated using 2-tailed t test). (K) Immunoblot from LNCaP cells treated with DHEA or R1881 with or without Enza after 4 Gy IR showing Enza suppresses DDR protein expression. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001