Up-regulation of telomerase activity in human pancreatic cancer cells after exposure to etoposide.
Telomerase plays a critical role in the development of cellular immortality and oncogenesis. Activation of telomerase occurs in a majority of human malignant tumours, and the relation between telomerase and vulnerability to drug-mediated apoptosis remains unclear. In this study, we demonstrate, for the first time, up-regulation of telomerase activity in human pancreatic cancer cells treated with etoposide, a topoisomerase II inhibitor. Exposure of MIA PaCa-2 cells to etoposide at various concentrations (1-30 microM) resulted in two- to threefold increases in telomerase activity. Up-regulation was detectable 24 h after drug exposure and was accompanied by enhanced expression of mRNA of the human telomerase reverse transcriptase. Telomerase activation was also observed in AsPC-1 and PANC-1 cells but not in KP-3 and KP-1N cells. Furthermore, we found a negative correlation between increased telomerase activity and the percentage of dead cells after etoposide treatment. These findings suggest the existence of an anti-apoptotic pathway through which telomerase is up-regulated in response to DNA damage. This telomerase activation pathway may be one of the mechanisms responsible for the development of etoposide resistance in certain pancreatic cancer cells.
Sato
N
N
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Mizumoto
K
K
Kusumoto
M
M
Nishio
S
S
Maehara
N
N
Urashima
T
T
Ogawa
T
T
Tanaka
M
M
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D017931:DNA Primers; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D005047:Etoposide; D019098:Telomerase