CNT1 Expression Influences Proliferation and Chemosensitivity in Drug-Resistant Pancreatic Cancer Cells

Abstract

Overcoming the inherent chemoresistance of pancreatic cancers remains a major goal of therapeutic investigations in this disease. In this study, we discovered a role for the human concentrative nucleoside transporter-1 (hCNT1; SLC28A1), a high-affinity pyrimidine nucleoside transporter, in determining the chemosensitivity of human pancreatic cancer cells to gemcitabine, the drug used presently as a standard of care. Compared with normal pancreas and pancreatic ductal epithelial cells, hCNT1 expression was frequently reduced in pancreatic tumors and tumor cell lines. In addition, hCNT1-mediated 3 H-gemcitabine transport was lower in pancreatic cancer cell lines and correlated with cytotoxic IC 50 estimations of gemcitabine. In contrast to gemcitabine-sensitive pancreatic cancer cell lines, MIA PaCa-2, a gemcitabine-resistant pancreatic cancer cell line, exhibited relatively restrictive, cell cycle-dependent hCNT1 expression and transport. hCNT1 translation was suppressed in the late G1-enriched MIA PaCa-2 cell population possibly in an miRNA-dependent manner, which corresponded with the lowest hCNT1-mediated gemcitabine transport during this phase. Although hCNT1 protein was induced during G1/S transition, increased hCNT1 trafficking resulted in maximal cell surface recruitment and transport-overshoot in the G2/M phase-enriched cell population. hCNT1 protein was directed predominantly to proteasomal or lysosomal degradation in S or G2/M phase MIA PaCa-2 cells, respectively. Pharmacological inhibition of hCNT1 degradation moderately increased cell surface hCNT1 expression and cellular gemcitabine transport in MIA PaCa-2 cells. Constitutive hCNT1 expression reduced clonogenic survival of MIA PaCa-2 cells and steeply augmented gemcitabine transport and chemosensitization. In addition to supporting a putative tumor suppressor role for hCNT1, our findings identify hCNT1 as a potential candidate to render drug-resistant pancreatic cancer cells amenable to chemotherapy. Cancer Res; 71(5); 1825-35. Ó2011 AACR.

Clinical and biological significance of Cdk10 in hepatocellular carcinoma

“…The chemosensitizing effect of Cdk10 may be associated with its ability to cause cell cycle arrest. Indeed, the cell-cycle mediated mechanisms for chemosensitivity have been described in many previous studies (Bhutia et al, 2011;Boni et al, 2010;Kalimutho et al, 2011). Further studies are required to elucidate the signaling pathways involved in the chemosensitization conferred by Cdk10.…”

Vasohibin 2 reduces chemosensitivity to gemcitabine in pancreatic cancer cells via JUN proto-oncogene dependent transactivation of ribonucleotide reductase regulatory subunit M2

“…Gemcitabine is taken up into cells primarily by human concentrative nucleoside transporter 1 and 3 (hCNT1 and hCNT3) and by human equilibrative nucleoside transporter (hENT1) [18]. The expression of these nucleoside transporters is correlated with chemosensitivity and patient survival [19][20][21][22][23]. After being taken into the cells, gemcitabine is activated by deoxycytidine (dCK) [24,25].…”

CXCR4/Let-7a Axis Regulates Metastasis and Chemoresistance of Pancreatic Cancer Cells Through Targeting HMGA2

“…Currently, GEM is still thought as the standard drug to treat pancreatic cancer [3, 8], however, not all cases respond similarly to GEM due to primary and acquired drug resistance. Therefore, it is an important field of fully understanding the mechanism underlying the drug resistance.…”