Dysregulated Cell Signaling Pathways in Prostate Tumoral Plasticity-Checkpoints

Objectives: Deregulated plasticity is involved in initiation, progression, metastasis, and resistance to therapy of various cancers. Our study aimed to present new checkpoints involved in complex biological processes that sustain epithelial-mesenchymal transition (EMT) variability and heterogeneity in prostate tumor cell plasticity. Methods: Dysregulated cell signaling pathways involved in prostate EMT heterogeneity were analyzed by intrinsic and extrinsic factors such as cell cycle phases by propidium iodide (PI) stain, apoptosis by caspase-3/7 biochemical cascade DEVDase enzyme activity by Magic Red stain (DEVD-MR)/propidium iodide stain, autophagy and nuclear shrinkage by Hoechst/acridine orange stain, evasion of immune surveillance by GPIba platelet glycoprotein conjugated with phycoerythrin (CD42b-PE) stain, oxidative stress by total reactive oxygen species (ROS) count by flow cytometry. Adaptation of the microenvironment involved in prostate EMT heterogeneity was analyzed by immunohistochemistry (IHC). Results: In our study, in benign prostatic hyperplasia (BPH) tissue samples, the low S-proliferative phase category of the cell cycle (SH: <7%) represents an independent predictor and a favorable prognostic biomarker for patient survival, as it is reported to dysregulate cell signaling pathways that characterize EMT heterogeneity. In prostate cancer tissue samples (PCa), the high S-proliferative phase category of the cell cycle (SCA, >12%) had an unfavorable prognostic role in patient survival rate, characteristically for EMT heterogeneity and aggressive phenotype involved in prostate tumoral cell plasticity, serving as a dependent predictor for the molecular mechanisms network, including late apoptosis, necrosis, autophagy, evasion of immune surveillance, cell cycle arrest in G0/G1 or G2/M phases, and oxidative stress. Conclusion: Low and high S-proliferative phase categories of the cell cycle, dysregulated early, late apoptosis via caspase-3/7 signaling pathway represent important checkpoints involved in EMT heterogeneity, and serve as independent or dependent predictor biomarkers for BPH and PCa patient prognostic survival rates, targeting personalized cancer therapy development.