RNA interference targeting ETS-1 downregulates RRM2 and enhances gemcitabine sensitivity in pancreatic cancer cells

Abstract

Aberrant expression of the Ets-1 transcription factor is increasingly associated with the progression of several human cancers. Previously we reported Ets-1 over-expression in gemcitabine resistance pancreatic cancer cell lines. In the present study, we identified Ribonucleotide reductase–M2 subunit, a key enzyme involved in the DNA synthesis is elevated in gemcitabine-resistant PANC1 cells. Silencing of Ets-1 expression in resistant cell line diminishes the Ribonucleotide reductase–M2 expression. The RAS/ERK pathway is commonly activated in carcinomas and promotes oncogenesis by altering transcriptional programs. Ets-1 silencing abrogates the expression of Ribonucleotide reductase–M2 levels in parental cells treated with epidermal growth factor to further activate the RAS/ERK pathway. Our findings clearly demonstrate the involvement of RAS/ERK-mediated Ets-1 pathway in the development of gemcitabine resistance by over-expressing Ribonucleotide reductase–M2.