Phytohormone Signaling Induces Dormancy and Apoptosis in Prostate Cancer Disseminated Tumor Cells

Abstract

Prostate cancer (PCa) remains a major health concern, ranking as the second leading cause of cancer-related deaths in men in the United States. The dissemination of tumor cells (DTCs) from the prostate, their entry into circulation, and subsequent skeletal metastasis involve complex mechanisms that are not fully elucidated. Notably, DTCs demonstrate a remarkable ability to home to the hematopoietic stem cell niche within bone marrow, where they may remain dormant for years. Key signaling pathways implicated in DTC dormancy include TGF-?, BMP4/BMP7, GAS6/TAM receptors, and Wnt5a, each influencing cell cycle arrest, survival, and phenotype adaptation. Recent research has explored analogies between dormancy mechanisms in cancer and plant biology, particularly focusing on phytohormones such as abscisic acid (ABA) and gibberellins, which regulate plant stress responses and developmental dormancy. While plants utilize PYR1/PYL/RCAR receptors for ABA, mammals rely on LANCL2 and PPAR?. This study evaluated the effects of ABA, gibberellic acid, and the ABA agonist pyrabactin on human and murine PCa cell lines. Results demonstrated that gibberellic acid lacked proliferative effects and could not counteract ABA-induced growth arrest. In contrast, pyrabactin potently induced growth arrest and apoptosis, activating SMAC/Diablo cell death pathways independently of LANCL2 and PPAR? signaling. Further, the activity of ABA and pyrabactin depended on cellular uptake via SLC4AE2 and SLC4A3 anion exchangers; downregulation of these transporters partially reversed their inhibitory effects. These findings suggest a mechanistic parallel between phytohormone-induced dormancy in plants and regulated dormancy and apoptosis in PCa, opening new avenues for therapeutic targeting of dormancy pathways in cancer metastasis.