01. ATPase β subunit inhibition provides a target for immuotherapy in hematologic malignancies The cell surface ATPase β subunit

acts as a high-density lipoprotein (HDL) receptor, through binding of apolipoprotein A-I in hepatocytes, and also regulates lipoprotein internalization in endothelial cells [21]; however the effects downstream of the cell surface ATPase β subunit remain to be determined. ATPase β subunits have been Selleck Foretinib detected on the membrane of tumor cells, raising the possibility that the structure of the β subunit protein on the cell surface may perform a different function to the inner mitochondrial protein structure. Our findings indicate that ectopic expression of the ATPase β subunit is a tumor-associated antigen in hematological malignancies. Although the function of the cell surface ATPase β subunit requires further study, this

study implies that the ATPase β subunit plays an important role in cancer cell proliferation and apoptosis. Our findings are in agreement with previous studies which have indicated that angiostatin, plasminogen kringle 1–5 (K1–5), McAb against the ATPase β subunit [3, 35] and small molecular inhibitors [1, 36] can bind to ATP synthase on the cell surface and inhibit endothelial cell proliferation, migration, trigger apoptosis [3–6, 10, 14, 19]. Cell surface ATP synthase is more active at a low extracellular pH [21]; therefore, ectopic expression of the ATPase β subunit may play an important role in the survival of cells suffering an energy shortage or during treatment with chemotherapy drugs, indicating cell surface ATP synthase may play important Amobarbital role in the development and treatment resistance Veliparib solubility dmso of hematological malignancies. Our study suggests that abnormal cell surface expression of ecto-F1F0-ATPase β subunit may provide a potential target for cancer immunotherapy in hematological malignancies. F1F0 ATP synthase was recently reported to be a co-chaperone

of heat shock protein Hsp90, as F1F0 ATP synthase co-immunoprecipitates with Hsp90 and Hsp90-client proteins in cell lysate from MCF-7, T47D, MDA-MB-453 and HT-29 cancer cells [37]. Heat shock proteins are often overexpressed in human malignancies, including AML. Hsp90 is the major chaperone required for stabilization of the multiple oncogenic kinases involved in the development of AML [38]. Hsp90 client proteins are also involved in the regulation of apoptosis, proliferation, autophagy and cell cycle progression, and several hsp90 client proteins are considered to be possible therapeutic targets for the treatment of AML [39]. Hsp90 inhibitors could be used as single agents or potentially, in combination with other targeted treatments such as a functional ATP synthase β subunit antibody. This study indicates that clinical focus of hsp90 inhibitors and F1F0-ATP β subunit synthase functional antibodies should be directed towards hematological malignancies, as well as solid tumors and malignant melanoma.