Tumor cells often hijack metabolic pathways to promote tumor growth and chemoresistance. Recent studies by our group show that human angiosarcomas and canine hemangiosarcomas express β-adrenergic receptors (β-ARs). Treatment with β-AR antagonists (beta blockers) inhibited tumor growth and sensitized cells to chemotherapy agents. Because β-ARs modulate the expression of the co-transcription factor PGC-1α, a key regulator of gluconeogenesis, mitochondrial metabolism, and fatty acid oxidation, expression of PGC-1α may be essential for sarcoma growth. Furthermore, chemoresistance has been shown to induce PGC-1α-dependent increases in mitochondrial metabolism and promote tumor cell survival, leading us to hypothesize that knockdown of PGC-1α would mimic the effects of beta blockade and increase the sensitivity of angiosarcoma and hemangiosarcoma cells to chemotherapy. We found that non-specific and receptor-specific β-AR antagonists reduced the viability of AS5 cells; however, an inhibitor specific for the β3-AR reduced viability to the greatest extent. Treatment of AS5 cells with the generic beta blocker, propranolol, and the chemotherapy drug, doxorubicin, sensitized AS5 cells to chemotherapy when compared to doxorubicin treatment alone. Propranolol also reduced the expression of PGC-1α, and knockdown of PGC-1α with siRNAs reduced the expression of the co-transcription factor. Our data suggest that β-AR signaling is important for angiosarcoma cell viability, and that beta blockers used in combination with standard-of-care chemotherapies may increase therapeutic efficacy. Knockdown of PGC-1α in angiosarcoma and hemangiosarcoma cell lines followed by treatment with doxorubicin will need to be performed to confirm the role of PGC-1α in chemoresistance.
This research was supported by CFANS Research Apprenticeship Program, Sarcoma Foundation of America, Morris Animal Foundation, and the Undergraduate Research Opportunities Program (UROP).
Fox, Kathryn; Dickerson, Erin.
Beta Adrenergic Signaling Promotes Drug Resistance in Sarcomas.
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