Gene expression profiling of adenosine triphosphate-binding cassette transporters in response to K-ras activation and hypoxia in human pancreatic cancer cell cultures.
OBJECTIVE
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.
Lo
Maisie
M
Department of Cancer Genetics, British Columbia Cancer Agency, University of British Columbia,Vancouver, British Columbia, Canada.
Tsao
Ming-Sound
MS
Hedley
David
D
Ling
Victor
V
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D014750:Vincristine / Q000494:pharmacology
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D014750:Vincristine