Decreased expression of B7-H3 reduces the glycolytic capacity and sensitizes breast cancer cells to AKT/mTOR inhibitors
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Caroline E. Nunes-Xavier1, Karine Flem Karlsen1, Christina Tekle1, Cathrine Pedersen2, Tove Øyjord1, Vesa Hongisto3, Jahn M. Nesland4, Ming Tan5, Kristine Kleivi Sahlberg 6,7, Øystein Fodstad1,8
1Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
2Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
3Misvik Biology Oy, Turku, Finland
4Department of Pathology, Oslo University Hospital Radiumhospitalet, Oslo, Norway
5Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
6Department of Research, Vestre Viken, Drammen, Norway
7K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
8Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Caroline E. Nunes-Xavier, e-mail: [email protected]
Keywords: CD276/B7-H3, breast cancer cells, API-2, everolimus, glycolysis
Received: June 19, 2015 Accepted: December 29, 2015 Published: January 12, 2016
B7 family proteins are important immune response regulators, and can mediate oncogenic signaling and cancer development. We have used human triple-negative breast cancer cell lines with different expression levels of B7-H3 to evaluate its effects on the sensitivity to 22 different anticancer compounds in a drug screen. API-2 (triciribidine) and everolimus (RAD-001), two inhibitors that target the PI3K/AKT/mTOR pathway, showed enhanced inhibition of cell viability and proliferation in B7-H3 knockdown tumor cells compared to their B7-H3 expressing counterparts. Similar inhibition was seen in control cells treated with an anti-B7-H3 monoclonal antibody. In B7-H3 overexpressing cells, the effects of the two drugs were reduced, supported also by in vivo experiments in which B7-H3 overexpressing xenografts were less sensitive to everolimus than control tumors. In API-2 and everolimus-treated B7-H3 overexpressing cells, phospho-mTOR levels were decreased. However, phosphorylation of p70S6K was differentially regulated in B7-H3 cells treated with API-2 or everolimus, suggesting a different B7-H3-mediated mechanism downstream of mTOR. Both API-2 and everolimus decreased the glycolysis of the cells, whereas knockdown of B7-H3 decreased and B7-H3 overexpression increased the glycolytic capacity. In conclusion, we have unveiled a previously unknown relationship between B7-H3 expression and glycolytic capacity in tumor cells, and found that B7-H3 confers resistance to API-2 and everolimus. The results provide novel insights into the function of B7-H3 in cancer, and suggest that targeting of B7-H3 may be a novel alternative to improve current anticancer therapies.
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