Cancer cells have a proliferative advantage by utilizing intermediates of aerobic glycolysis (Warburg-effect) for their macromolecule synthesis. Although the exact causes of this Warburg-effect are unclear, high osmotic stress in solid tumor microenvironment is considered as one of the important factors. Oleanolic acid (OA) is known to exert anti-inflammatory and anti-cancer effect. In our current studies, using breast cancer cell lines, we determined the protective role of OA in high salt mediated osmotic stress induced cancer growth. Hypertonic (0.16M NaCl) culture conditions enhanced the cancer cell growth (26%, p<0.05) and aerobic glycolysis as marked by increased glucose consumption (34%, p<0.05) and lactate production (25%, p<0.05) over untreated cells. This effect was associated with increased expression and activity of key rate-limiting enzymes of aerobic glycolysis, namely, hexokinase, pyruvate kinase-typeM2 and lactate dehydrogenase-A. Interestingly, this high salt mediated enhanced expression of aerobic glycolytic enzymes was efficiently reversed by OA along with decreased cancer cell proliferation. In cancer cells, enhanced aerobic glycolysis is associated with decreased mitochondrial activity and mitochondrial-associated caspase activity. As expected, high salt further inhibited the mitochondrial related cytochrome oxidase and caspase-3 activity. However, OA efficiently reversed the high salt mediated inhibition of cytochrome oxidase, caspase activity and pro-apoptotic Bax expression, thus suggesting that OA induced mitochondrial activity and enhanced apoptosis. Taken together, our data indicate that OA efficiently reverses the enhanced Warburg-like metabolism induced by high salt mediated osmotic stress along with potential application of OA in anti-cancer therapy.
Previous phase I DNA-vaccine based clinical trials using Mammaglobin-A (Mam-A), a human breast tumor associated antigen (TAA), demonstrated that this agent was safe and efficient at treating patients with stage IV breast cancer. The long-term success of cancer vaccines is limited by the diminished expression of human leukocyte antigen (HLA) class I molecules in the tumor microenvironment. The current study assessed the impact of various selenocompounds on the expression of HLA class I molecules in THP-1 cells, an apparent proficient antigen that presents a human monocyte-like cell line, and their eventual activation of MamA2.1 (HLA-A2 immunodominant epitope of MamA) specific cytotoxic CD8 + T lymphocytes (CTLs). The results revealed that, following treatment with methylselenol producing compounds [methylselenic acid (MSA) and dimethylselenide (DMDSe)], the expression of HLA class-I was increased and components involved with the antigen presentation machinery of THP-1 cells were upregulated.
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