Activation of HIF-1a by d-opioid receptors induces COX-2 expression in breast cancer cells and leads to paracrine activation of vascular endothelial cells

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Abstract

Opioids promote tumor angiogenesis in mammary malignancies, but the underlying signaling mechanism is largely unknown. The current study investigated the hypothesis that stimulation of d-opioid receptors (DOR) in breast cancer (BCa) cells activates the hypoxia-inducible factor 1a (HIF-1a), which triggers synthesis and release of diverse angiogenic factors. Immunoblot-ting revealed that incubation of human MCF-7 and T47D breast cancer cells with the DOR agonist D-Ala2,D-Leu5-enkephalin (DADLE) resulted in a transient accumulation and thus activation of HIF-1a. DADLE-induced HIF-1a activation preceded PI3K/Akt stimulation and was blocked by the DOR antagonist naltrindole and naloxone, pertussis toxin, different phosphoinositide 3-kinase (PI3K) inhibitors, and the Akt inhibitor Akti-1/2. Whereas DADLE exposure had no effect on the expression and secretion of vascular endothelial growth factor (VEGF) in BCa cells, an increased abundance of cyclooxygenase-2 (COX-2) and release of prostaglandin E2 (PGE2) was detected. DADLE-induced COX-2 expression was also observed in three-dimensional cultured MCF-7 cells and impaired by PI3K/Akt inhibitors and the HIF-1a inhibitor echinomycin. Supernatant from DADLE-treated MCF-7 cells triggered sprouting of endothelial (END) cells, which was blocked when MCF-7 cells were pretreated with echinomycin or the COX-2 inhibitor celecoxib. Also no sprouting was observed when END cells were exposed to the PGE2 receptor antagonist PF-04418948. The findings together indicate that DOR stimulation in BCa cells leads to PI3K/Akt-dependent HIF-1a activation and COX-2 expression, which trigger END cell sprouting by paracrine activation of PGE2 receptors. These findings provide a potential mechanism of opioid-driven tumor angiogenesis and thus therapeutic targets to combat the tumor-angiogenic opioid effect.

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Schoos, A., Gabriel, C., Knab, V. M., & Fux, D. A. (2019). Activation of HIF-1a by d-opioid receptors induces COX-2 expression in breast cancer cells and leads to paracrine activation of vascular endothelial cells. Journal of Pharmacology and Experimental Therapeutics, 370(3), 480–489. https://doi.org/10.1124/jpet.119.257501

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