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.

Group members

Maria Shoshan, PhD, Associate Professor
Nicole Bezuidenhout, PhD student

Selected publications

PGC1α: Friend or Foe in Cancer?
Mastropasqua F, Girolimetti G, Shoshan M
Genes (Basel) 2018 Jan;9(1):

On mitochondrial metabolism in tumor biology.
Shoshan M
Curr Opin Oncol 2017 01;29(1):48-54

Metabolic profiling of epithelial ovarian cancer cell lines: evaluation of harvesting protocols for profiling using NMR spectroscopy.
Engskog M, Björklund M, Haglöf J, Arvidsson T, Shoshan M, Pettersson C
Bioanalysis 2015 ;7(2):157-66

Expression of mitochondrial regulators PGC1α and TFAM as putative markers of subtype and chemoresistance in epithelial ovarian carcinoma.
Gabrielson M, Björklund M, Carlson J, Shoshan M
PLoS ONE 2014 ;9(9):e107109

Protein markers of cancer-associated fibroblasts and tumor-initiating cells reveal subpopulations in freshly isolated ovarian cancer ascites.
Wintzell M, Hjerpe E, Åvall Lundqvist E, Shoshan M
BMC Cancer 2012 Aug;12():359

Repeated cisplatin treatment can lead to a multiresistant tumor cell population with stem cell features and sensitivity to 3-bromopyruvate.
Wintzell M, Löfstedt L, Johansson J, Pedersen AB, Fuxe J, Shoshan M
Cancer Biol. Ther. 2012 Dec;13(14):1454-62

Cisplatin-induced nitrosylation of p53 prevents its mitochondrial translocation.
Hernlund E, Kutuk O, Basaga H, Linder S, Panaretakis T, Shoshan M
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.
Hernlund E, Hjerpe E, Avall-Lundqvist E, Shoshan M
Mol. Cancer Ther. 2009 Jul;8(7):1916-23