The release of pro-apoptotic proteins from mitochondria is a key event in cell death signalling that is regulated by Bcl-2 family proteins. Cleavage of the BH3-only protein Bid by multiple proteases leads to the formation of truncated Bid (tBid) which, in turn, promotes the insertion and oligomerization of Bcl-2 family protein BAX into the outer membrane of mitochondria, resulting in pore formation and release of proteins residing in the intermembrane space. To this date, our group is studying the mechanism how BAX is targeted to the outer membrane of mitochondria.
Recently, we have shown that both in primary and cultured cells, the association of BAX with mitochondria is controlled by its S-palmitoylaton at Cys-126. A lack of BAX palmitoylation reduces BAX mitochondrial translocation, BAX oligomerization, caspase activity and apoptosis. Ectopic expression of specific palmitoyl transferases in cultured healthy cells increases BAX S-palmitoylation and accelerated apoptosis, wheras malignant tumor cells showes reduced BAX S-palmitoylation, consistent with their reduced BAX-mediated proapoptotic activity. Based on these findings we are now focussing on new concepts fighting malignant tumor cells by stimulating palmitoylation of BAX.
Gorska-Ponikowska, M., Batian, P., Zauszkiewicz-Pawlak, A., Ploska, A., Zubrzycki, A., Kuban-Jankowska, A., Nussberger, S., Kalinowski, L. & Kmiec, Z. Regulation of mitochondrial dynamics in 2-methoxyestradiol-mediated osteosarcoma cell death. Scientific Reports, 1-12 doi:10.1038/s41598-020-80816-x (2021)
Gorska-Ponikowska, M., Kuban-Jankowska, A., Eisler, S., Perricone, U., Lo Bosco, G., Barone. G. & Nussberger, S. 2-Methoxyestradiol affects mitochondrial biogenesis and succinate complex flavoprotein subunit dehydrogenase A in osteosarcoma cancer cells. Cancer Genomics Proteomics 15:73-89 (2018)
Gorska-Ponikowska, M., Kuban-Jankowska, A., Daca, A. & Nussberger, S. 2-Methoxyestradiol reverses the pro-carcinogenic effect of L-lactate in osteosarcoma 143B cells. Cancer Genomics Proteomics 14:483-493 (2017)
Fröhlich, M., Dejanovic, B., Kashkar, H., Schwarz, G. & Nussberger, S. S-palmitoylation represents a novel mechanism regulating the mitochondrial targeting of BAX and initiation of apoptosis. Cell Death & Disease. 5 e1057:1-9 (2014)