Abstract
The purpose of this work was to reveal the metabolic features of mitochondria that might be essential for inhibition of apoptotic potential in prostate cancer cells. We studied mitochondria isolated from normal prostate epithelial cells (PrEC), metastatic prostate cancer cell lines LNCaP, PC-3, DU145; and non-prostate cancer cells - human fibrosarcoma HT1080 cells; and normal human lymphoblastoid cells. PrEC cells contained 2 to 4 times less mitochondria per gram of cells than the three PC cell lines. Respiratory activities of PrEC cell mitochondria were 5-20-fold lower than PC mitochondria, depending on substrates and the metabolic state, due to lower content and lower activity of the respiratory enzyme complexes. Mitochondria from the three metastatic prostate cancer cell lines revealed several features that are distinctive only to these cells: low affinity of Complex I for NADH, 20-30 mV higher electrical membrane potential (ΔΨ). Unprotected with cyclosporine A (CsA) the PC-3 mitochondria required 4 times more Ca2+ to open the permeability transition pore (mPTP) when compared with the PrEC mitochondria, and they did not undergo swelling even in the presence of alamethicin, a large pore forming antibiotic. In the presence of CsA, the PC-3 mitochondria did not open spontaneously the mPTP. We conclude that the low apoptotic potential of the metastatic PC cells may arise from inhibition of the Ca2+-dependent permeability transition due to a very high ΔΨ and higher capacity to sequester Ca2+. We suggest that due to the high ΔΨ, mitochondrial metabolism of the metastatic prostate cancer cells is predominantly based on utilization of glutamate and glutamine, which may promote development of cachexia.
Highlights
Prostate cancer is the major cause of male cancer death in the age range of 55-74, and above age 75 it is the second greatest cause of death in North American men after lung and bronchus cancer [1,2]
We report here that mitochondria from the three metastatic prostate cancer cell lines have a number of distinct metabolic features: a 20 to 30 mV higher electrical membrane potential (ΔΨ), low affinity of the Complex I to NADH, higher resistance to Ca2+ loads, and an unusual response to cyclosporine A and the pore forming antibiotic Alamethicin, when compared with the prostate epithelial cells (PrEC) and normal human lymphoblastoid cells (HLB) mitochondria
The highest yields among the prostate cancer cells were obtained with LNCaP cells, and with fibrosarcoma cells (HT1080C) and normal human lymphoblastoid cells (HLB)
Summary
Prostate cancer is the major cause of male cancer death in the age range of 55-74, and above age 75 it is the second greatest cause of death in North American men after lung and bronchus cancer [1,2]. All men with advanced disease, who went through androgen deprivation therapies, eventually die because of development of androgenindependent metastatic prostate cancer [1,3,4]. There is a large body of data, which indicates that progression of both primary and metastatic prostatic tumors is determined by the loss of the cell’s apoptotic potential [6,7,8]. The participation of mitochondria in apoptosis has been substantiated by a large number of reports describing proapoptotic mitochondrial alterations, such as production of reactive oxygen species (ROS), depletion of ATP, and induction of the mitochondrial permeability transition pore (mPTP) [9,10,11].
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