Collagen/beta1 integrin signaling upregulates the ABCC1/MRP-1 transporter in an ERK/MAPK-dependent manner

The mechanisms by which β1 integrins regulate chemoresistance of cancer cells are still poorly addressed. In this study, we report that collagen/β1 integrin signaling inhibits doxorubicin-induced apoptosis of Jurkat and HSB2 leukemic T cells by upregulating the expression and function of the ATP Binding Cassette C 1 (ABCC1) transporter, also known as Multi-drug resistance-associated protein 1 (MRP-1). We found that collagen but not fibronectin reduces intracellular doxorubicin content and upregulates the expression levels of ABCC1. Inhibition and knockdown studies showed that upregulation of ABCC1 is necessary for collagen-mediated reduction of intracellular doxorubicin content, and for collagenmediated inhibition of doxorubicin-induced apoptosis. We also demonstrate that activation of the ERK/MAPK signaling pathway is involved in collagen-induced reduction of intracellular doxorubicin accumulation, in collagen-induced upregulation of ABCC1 expression levels, and in collagen-mediated cell survival. Finally, collagen-mediated upregulation of ABCC1 expression and function also requires actin polymerization. Taken together our results indicate for the first time that collagen/β1 integrin/ERK signaling upregulates the expression and function of ABCC1 and suggest that its activation could represent an important pathway in cancer chemoresistance. Thus, simultaneous targeting of collagen/β1 integrin and ABCC1 may be more efficient in preventing drug resistance than targeting each pathway alone.