Key points are not available for this paper at this time.
// Caroline E. Nunes-Xavier 1 , Karine Flem Karlsen 1 , Christina Tekle 1 , Cathrine Pedersen 2 , Tove Øyjord 1 , Vesa Hongisto 3 , Jahn M. Nesland 4 , Ming Tan 5 , Kristine Kleivi Sahlberg 6, 7 , Øystein Fodstad 1, 8 1 Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway 2 Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway 3 Misvik Biology Oy, Turku, Finland 4 Department of Pathology, Oslo University Hospital Radiumhospitalet, Oslo, Norway 5 Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA 6 Department of Research, Vestre Viken, Drammen, Norway 7 K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway 8 Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway Correspondence to: Caroline E. Nunes-Xavier, e-mail: carnun@rr-research.no Keywords: CD276/B7-H3, breast cancer cells, API-2, everolimus, glycolysis Received: June 19, 2015 Accepted: December 29, 2015 Published: January 12, 2016 ABSTRACT 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.
Nunes‐Xavier et al. (Tue,) studied this question.