The therapeutic options for castration-resistant prostate cancer (CRPC) are still limited. Natural bioactive compounds were shown to possess pro-death properties in different tumors. We previously reported that δ-tocotrienol (δ-TT) induces apoptosis, paraptosis and autophagy in CRPC cells. Here, we investigated whether δ-TT might exert its activity by impairing mitochondrial functions. We demonstrated that, in PC3 and DU145 cells, δ-TT impairs mitochondrial respiration and structural dynamics. In both cell lines, δ-TT triggers mitochondrial Ca2+ and ROS overload. In PC3 cells, both Ca2+ and ROS mediate the δ-TT-related anticancer activities (decrease of cell viability, apoptosis, paraptosis, autophagy and mitophagy). As expected, in autophagy-defective DU145 cells, Ca2+ overload was involved in δ-TT-induced pro-death effects but not in autophagy and mitophagy. In this cell line, we also demonstrated that ROS overload is not involved in the anticancer activities of δ-TT, supporting a low susceptibility of these cells to ROS-related oxidative stress. Taken together, these data demonstrate that, in CRPC cells, δ-TT triggers cell death by inducing mitochondrial functional and structural impairments, providing novel mechanistic insights in its antitumor activity.

Mitochondrial functional and structural impairment is involved in the antitumor activity of δ-tocotrienol in prostate cancer cells / F. Fontana, M. Raimondi, M. Marzagalli, M. Audano, G. Beretta, P. Procacci, P. Sartori, N. Mitro, P. Limonta. - In: FREE RADICAL BIOLOGY & MEDICINE. - ISSN 0891-5849. - 160(2020 Nov 20), pp. 376-390. [10.1016/j.freeradbiomed.2020.07.009]

Mitochondrial functional and structural impairment is involved in the antitumor activity of δ-tocotrienol in prostate cancer cells

F. Fontana
Primo
;
M. Raimondi
Secondo
;
M. Marzagalli
;
M. Audano
;
G. Beretta
;
P. Procacci
;
P. Sartori
;
N. Mitro
Penultimo
;
P. Limonta
Ultimo
2020

Abstract

The therapeutic options for castration-resistant prostate cancer (CRPC) are still limited. Natural bioactive compounds were shown to possess pro-death properties in different tumors. We previously reported that δ-tocotrienol (δ-TT) induces apoptosis, paraptosis and autophagy in CRPC cells. Here, we investigated whether δ-TT might exert its activity by impairing mitochondrial functions. We demonstrated that, in PC3 and DU145 cells, δ-TT impairs mitochondrial respiration and structural dynamics. In both cell lines, δ-TT triggers mitochondrial Ca2+ and ROS overload. In PC3 cells, both Ca2+ and ROS mediate the δ-TT-related anticancer activities (decrease of cell viability, apoptosis, paraptosis, autophagy and mitophagy). As expected, in autophagy-defective DU145 cells, Ca2+ overload was involved in δ-TT-induced pro-death effects but not in autophagy and mitophagy. In this cell line, we also demonstrated that ROS overload is not involved in the anticancer activities of δ-TT, supporting a low susceptibility of these cells to ROS-related oxidative stress. Taken together, these data demonstrate that, in CRPC cells, δ-TT triggers cell death by inducing mitochondrial functional and structural impairments, providing novel mechanistic insights in its antitumor activity.
Prostate cancer cells; δ-tocotrienol; Mitochondrial dysfunction; Mitophagy; Ca2+ overload; ROS generation;
Settore BIO/13 - Biologia Applicata
Settore BIO/10 - Biochimica
   Dipartimenti di Eccellenza 2018-2022 - Dipartimento di SCIENZE FARMACOLOGICHE E BIOMOLECOLARI
   MINISTERO DELL'ISTRUZIONE E DEL MERITO

   Useful experimental models for dissecting the molecular links between cancer development/progression and the obesity epidemic
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
   2015B7M39T_004
20-nov-2020
29-lug-2020
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/767745
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