Mechanisms of the resistance to the mitochondrial permeability transition in tumour cells

Abstract

Tumour cell mitochondria often have a high Ca 2+ threshold for induction of the mitochondrial permeability transition (MPT). The mechanisms of inhibited MPT are briefly reviewed. MPT stimulates the release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria. This is central in the signal pathways leading to apoptosis. Inhibited apoptosis may lead to excessive cell proliferation while induced apoptosis is the aim of cancer therapies. Also cell death by necrosis may result from impaired mitochondrial function due to MPT and the resulting decrease in cellular ATP levels. Many prooxidants trigger cell death by inducing MPT. Tumour cells may have greater resistance to prooxidants and free radicals formed also in radiation therapy. One mechanism for the inhibition of MPT could be increased expression of the Bcl-2 protein in tumour cells. We found this to be the case in Zajdela hepatoma mitochondria. Another mechanism could be the increased contents of Mg 2+ in tumour mitochondria, since Mg 2+ is an inhibitor of MPT. This was found to be the case in Ehrlich ascites tumour cell mitochondria. Other contributing factors could be inhibition of phospholipase A 2 by the Mg 2+, changes in the amounts and properties of the adenine nucleotide translocator and/or mitochondrial ATP synthase.