Abstract 3394: Participation of molecular iodine and PPARG in prostate cancer progression and neuroendocrine differentiation
Authors: de Oca Carlos Montes , Álvarez Lourdes , Aceves Carmen , Anguiano Brenda 
Published: March 2024

Introduction: Advanced prostate cancer (PCa) therapy is based on androgen deprivation; however, cancerous cells develop resistance, and can develop a highly aggressive neuroendocrine (NE) phenotype. Molecular iodine (I2) has antitumoral effects in breast cancer models, in which PPARG receptors represent the main mechanism of action described. In PCa though, PPARG is considered pro-tumoral and I2 effects have not been fully studied. Hence, the aim of this study was to analyze I2 individual and combined effects with androgen deprivation by using both androgen dependent (AD) and independent (AI), in vitro and in vivo PCa models.

Methods: In vitro. I2 effects in cell viability and invasion were analyzed in AD (LNCaP) and AI (DU145, PC3) PCa cells. LNCaP cells were also treated with androgen receptor (AR) antagonists. PPARG participation in I2 effects was assessed with GW9962 (antagonist) and rosiglitazone (agonist). NE phenotype was induced in LNCaP by prolonged culture under androgen-depleted conditions and was assessed by measuring the growth and length of neurite-like projections. RT-qPCR was employed to assess the expression of NE markers (SYP, ENO2), and lipogenic genes (FASN, SREBF1). In vivo. Eighteen weeks-old TRAMP mice were subjected to sham surgery or castration, and were provided or not with I2 (0.025%, drinking water) for four weeks. Prostates were subjected to histopathological analysis (H&E and Masson's trichrome) and IHC (AR, SYP, PPARG). Scoring systems were used to grade the severity of high proliferative intraepithelial lesions (HPIN), and desmoplasia.

Results: I2 decreased the cell viability and invasion capacity of all PCa cells tested, and when supplied with AR antagonists further enhanced their antiproliferative effects in LNCaP cells. I2 failed to induce the expression of PPARG target genes, and GW9662 did not prevent I2-induced decrease in cell viability. Like androgen deprivation, I2 also caused NE-like morphology in LNCaP cells, but unlike androgen deprived LNCaP cells, I2 treated cells had decreased expression of NE markers. In TRAMP mice, I2 increased the presence of HPIN, reduced nuclear AR protein detection, and had no effect on PPARG. As expected, castration reduced HPIN, caused epithelial atrophy and desmoplasia; decreased total AR levels and PPARG nuclear levels. However, the number of NE (SYP-positive) cells did not change. The addition of I2 to castration did not modify the score of epithelial lesions but increased the desmoplasia and the presence of NE cells.

Conclusions: I2 exhibited in vitro antineoplastic effects over epithelial cells, however, these effects did not translate into the in vivo model. PPARG did not seem to mediate I2 effects. Overall, our data suggest that tumoral microenvironment may interfere with I2 epithelial-specific antitumoral effects.

Funding: PAPIIT-UNAM (IN217223, IN202322) and CONAHCYT (774791).

Citation Format: Carlos Montes de Oca, Lourdes Álvarez, Carmen Aceves, Brenda Anguiano. Participation of molecular iodine and PPARG in prostate cancer progression and neuroendocrine differentiation [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 3394.