Decreased expression of B7-H3 reduces the glycolytic capacity and sensitizes breast cancer cells to AKT/mTOR inhibitors

Oncotarget
Caroline E Nunes-XavierØystein Fodstad

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 a...Continue Reading

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Citations

Apr 20, 2013·International Immunopharmacology·Xiao-Hua ShenGuo-Sheng Fu
May 18, 2017·Pigment Cell & Melanoma Research·Karine Flem-KarlsenCaroline E Nunes-Xavier
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Methods Mentioned

BETA
xenografts
xenografs
Protein Assay
Assay

Clinical Trials Mentioned

NCT01391143
NCT02475213
NCT01099644
NCT01502917
NCT00089245

Software Mentioned

ImageJ
MicroBeta Windows Workstation
GraphPad
GraphPad Prism

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