Preserving Transport Protein Activity Aids Fight Against Pancreatic Cancer

By increasing the activity of a membrane protein that transports compounds – including chemotherapeutic drugs – into cancer cells, researchers were able to demonstrate enhanced killing of pancreatic cancer cells.

The cells that comprise pancreatic tumors are notoriously resistant to chemotherapeutic agents. A major reason for this is the reduced function of the human concentrative nucleoside transporter-1 (hCNT1), a high-affinity pyrimidine nucleoside transporter that occurs in about two thirds of pancreatic tumors.

Investigators at the University of Georgia (Athens, USA) increased the expression of hCNT1 by using drugs or genetic means to prevent the degradation of this membrane protein by enzymes within the cancer cells. They reported in the March 1, 2011, issue of the journal Cancer Research that pharmacological inhibition of hCNT1 degradation moderately increased cell surface hCNT1 expression and cellular gemcitabine (the primary drug used to treat pancreatic cancer) transport in MIA PaCa-2 cells. Constitutive hCNT1 expression reduced survival of MIA PaCa-2 cells and steeply augmented gemcitabine transport.

"The transporter was failing to take up the drug, so there were a bunch of different drug-resistant tumor cells,” said senior author Dr. Rajgopal Govindarajan, assistant professor of pharmaceutical and biomedical sciences at the University of Georgia. "Therapies that restore hCNT1 could increase the effectiveness of the drug by helping carry the drug into the cell. We overexpressed this protein in tumor cells so that it is functional continuously throughout the cell cycle, and it took up a lot of the drug and facilitated tumor killing, so it shows potential for therapeutic aspects.”

Additionally, the investigators found that hCNT1 was likely regulated by micro-RNAs (miRNAs). "Micro-RNAs are clearly emerging as a new paradigm in gene regulation,” said Dr. Govindarajan. "We could potentially use micro-RNAs to increase hCNT1 expression and increase tumor-cell targeting of gemcitabine.”

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