Adrenaline induces chemoresistance in HT-29 colon adenocarcinoma cells

Abstract

Psychological distress and its ensuing chronic elevation of plasma catecholamines (adrenaline and noradrenaline) lead to poor response of tumors to chemotherapy, and constitute a poor prognostic factor for survival. Colorectal cancer patients suffer from various forms of psychological stress reflected in elevated plasma catecholamines, and their cancer cells express adrenergic receptors. Our objective was to investigate whether adrenergic activation contributes to the chemoresistance of colon cancers, and to explore the signal transduction pathway involved in the activation. The mRNA expression of the ABCB1 gene (previously MDR1) in human colon carcinoma HT-29 cell line was measured after treatment with an adrenergic receptor agonist (adrenaline) and various antagonists (propranolol, prazosin, and yohimbine). The function of P-glycoprotein, the protein product of the ABCB1 gene, was assessed by rhodamine 123 (Rh123)-retention assay, and chemosensitivity was determined by evaluating the cytotoxicity of 5-fluorouracil (5-FU) on the tumor cells. Increased ABCB1 mRNA expression and P-glycoprotein function levels in HT-29 cells by adrenaline was dose-dependent. This was accompanied by promotion of Rh123 efflux, and resistance to the growth-inhibiting effect of 5-FU in the tumor cells. The alpha2-adrenergic receptor antagonist yohimbine completely abolished the induction of ABCB1 mRNA, the stimulatory effect of adrenaline on Rh123 efflux, and the growth-inhibiting effect of 5-FU. The alpha1-adrenergic receptor and beta-adrenergic receptor antagonists did not inhibit the induction of ABCB1. The stimulating effects were coupled with extracellular receptor kinase 1/2 (Erk1/2) phosphorylation, but were not associated with protein kinase A activity. We conclude that adrenaline induces multidrug resistance in colon cancer cells by upregulating ABCB1 gene expression via alpha2-adrenergic receptors, and such effects were associated with the mitogen activated protein kinase (MAPK) pathway.