Author(s): Lo M, Tsao MS, Hedley D, Ling V
OBJECTIVES: Pancreatic cancer (PC) is hypoxic and highly resistant to conventional chemotherapy. We sought to determine whether K-ras oncogene and/or hypoxia can induce expression of drug resistance-promoting adenosine triphosphate-binding cassette (ABC) transporters in human PC cell lines.
METHODS: Immortalized near-normal human pancreatic ductal epithelial(HPDE) cells, HPDE cells expressing K-rasG12V oncogene, and PCcell lines (MIA PaCa-2, PANC-1, BxPC-3) were subjected to hypoxia and examined for messenger RNA expression of 48 ABC transporters. RESULTS: Mutant K-ras activation and/or hypoxia of HPDE cells led to induction of various ABC transporters. In the case of PC cell lines, no clear correlation was found between expression of constitutively active K-ras and global ABC transporter expression. Moreover, hypoxic treatment of PC cell lines had different effects on ABC transporter expression.Importantly, PC cell lines did not express the multidrug resistance 1 ABC transporter, a major mechanism of drug resistance. However, multi drug resistance 1 expression in the cells was up-regulated in response to continuous exposure to low doses of vincristine, indicating that drug resistance could be induced.
CONCLUSIONS: Expression of K-ras oncogene and hypoxia, as well as exposure to drugs, can contribute to drug resistance in PC cells.