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.
Highlights
The B7 family of immune receptors is considered essential in the regulation of the adaptive immune system, but its members are expressed in non-hemopoietic tissues and are emerging as important players in cancer [1].These proteins can be divided into three groups, according to the signals they transduce during T cell activation: I) co-stimulatory (e.g. B7-1 and B7-2); II) inhibitory (e.g. B7-H1); and III) co-stimulatory/inhibitory (e.g. B7-H3 and B7-H4) [2, 3]
We found that the effect of API-2 and everolimus (RAD-001), two small molecule inhibitors targeting the PI3K/AKT/mTOR pathway, was partially dependent on B7-H3 expression
Decreased expression and inhibiton of B7-H3 increases the sensitivity of breast cancer cells to AKT/mTOR inhibitors API-2 and everolimus
Summary
The B7 family of immune receptors is considered essential in the regulation of the adaptive immune system, but its members are expressed in non-hemopoietic tissues and are emerging as important players in cancer [1] These proteins can be divided into three groups, according to the signals they transduce during T cell activation: I) co-stimulatory (e.g. B7-1 and B7-2); II) inhibitory (e.g. B7-H1); and III) co-stimulatory/inhibitory (e.g. B7-H3 and B7-H4) [2, 3]. The precise molecular basis for the functional role of B7-H3 in cancer remains unclear In this context, we have identified an oncogenic non-immunological role of B7-H3 in melanoma and breast cancer, which promotes metastasis and resistance to chemotherapy. These effects could be exerted through regulation of proteins in the JAK2/STAT3 signaling pathways, as well as by modulating the expression of cytokines and other metastasis-associated genes [12, 17]
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