Maria Shoshan's Group
Tumor cell energy metabolism, progression and chemotherapy: involvement of mitochondria. To maintain their growth rate, tumor cells must produce more energy and more building blocks than normal cells. While normal cells produce energy (ATP) by oxidative phosphorylation (OxPhos) in mitochondria, tumor cells are more dependent on glycolysis for ATP, and on metabolism of fatty acids and amino acids. The altered metabolism contributes to enhanced levels of precursors for DNA and protein syntheses, and to metastasis and resistance to therapy and apoptosis. Interestingly, there is increasing evidence for cancer-specific mutations in mitochondrial DNA and a role for altered electron transport chain components in resistance and metastasis.
Platinum-based (Pt) chemotherapeutic drugs typically target nuclear DNA and induce reactive oxygen species via mitochondria. However, mitochondria might also be targets per se. Mito-DNA is highly sensitive to damage leading to deletions which in turn have been suggested to promote more aggressive phenotypes.
Using in vitro methodologies as well as clinical samples, we have four main lines of investigation:
1. Pharmacological modulators of energy metabolism (MEMs) as potentiators of chemotherapy effects: can they enhance cell death and/or block dedifferentiation? Can they target chemoresistant and tumorigenic cancer stem cells?
2. Mitochondrial damage, in particular to mitochondrial DNA, in tumor progression and as a consequence of chemotherapies.
3. Mitochondria as targets of platinum-based (Pt) chemotherapy:
a. in tumor cells, in particular in resistant cells: how do Pt drugs affect mitochondria and, subsequently, tumor cell phenotype?
b. in normal cells, where Pt drugs exert their dose-limiting toxicities; in particular, inner ear hair cells and proximal tubule cells which are highly dependent on mitochondria. One goal here is to develop protective strategies.
4. The role of estrogen receptors in regulation of mitochondrial function, and in the efficacy and toxicity of Pt chemotherapy.
We are funded by Cancerfonden, Vetenskapsrådet, Radiumhemmets Forskningsfonder and others.
Repeated cisplatin treatment can lead to a multiresistant tumor cell population with stem cell features and sensitivity to 3-bromopyruvate.
Cancer Biol. Ther. 2012 Dec;13(14):1454-62
Cisplatin-induced nitrosylation of p53 prevents its mitochondrial translocation.
Free Radic. Biol. Med. 2009 Jun;46(12):1607-13
Ovarian carcinoma cells with low levels of beta-F1-ATPase are sensitive to combined platinum and 2-deoxy-D-glucose treatment.
Mol. Cancer Ther. 2009 Jul;8(7):1916-23