APOPTOSIS AND PARAPTOSIS, INVOLVING ENDOPLASMIC RETICULUM STRESS, AUTOPHAGY AND MITOCHONDRIAL DYSFUNCTION, ARE INDUCED BY DELTA-TOCOTRIENOL IN PROSTATE CANCER CELLS

Castration resistant prostate cancer (CRPC) is the most aggressive form of prostate cancer with still limited therapeutic outcomes due to the development of resistance to standard treatments. Unraveling the molecular mechanisms at the basis of the pro-death activity of novel anticancer compounds is necessary to increase the treatment strategies for this pathology. Here, we demonstrated that \u3b4-tocotrienol (\u3b4-TT, a vitamin E derivative) can induce apoptosis in human CRPC cell lines (PC3 and DU145) through modulation of the endoplasmic reticulum (ER) stress-autophagy axis. In these cells, \u3b4-TT also triggers paraptosis, a non-canonical cell death mechanism characterized by cytoplasmic vacuolation resulting from mitochondrial/ER swelling and requiring protein synthesis. Mechanistically, we observed that \u3b4-TT downregulates OXPHOS protein levels and inhibits mitochondrial respiration in PC3 and DU145 cells, leading to reduced oxygen consumption, ATP depletion and AMPK activation. Moreover, \u3b4-TT treatment resulted in Ca2+ homeostasis alteration and ROS production, followed not only by apoptosis/paraptosis but also by mitochondrial fission and mitophagy. Taken together, these data demonstrate that in CRPC \u3b4-TT can trigger both apoptosis and paraptosis, involving ER stress and autophagy. In addition, they suggest that \u3b4-TT specifically alters mitochondrial morphology and function, inducing Ca2+ overload- and oxidative stress-mediated cell death