Gene expression profiles of necrosis and apoptosis induced by 5-fluoro-2'-deoxyuridine.
5-Fluoro-2'-deoxyuridine (FUdR), a potent anticancer agent, exerts its effects by inhibiting thymidylate synthase, an essential machinery for DNA synthesis in cell proliferation. Also, cell death is caused by FUdR, primarily due to an imbalance in the nucleotide pool resulting from this enzyme inhibition. We have investigated the cancer cell death induced by FUdR, focusing on its molecular mechanisms. Using mouse mammary tumor FM3A cell lines, the original clone F28-7 and its variant F28-7-A cells, we previously reported an interesting observation that FUdR induces a necrotic morphology in F28-7, but induces, in contrast, an apoptotic morphology in F28-7-A cells. In the present study, to understand the molecular mechanisms underlying these differential cell deaths, i.e., necrosis and apoptosis, we investigated the gene expression changes occurring in these processes. Using the cDNA microarray technology, we found 215 genes being expressed differentially in the necrosis and apoptosis. Further analysis revealed differences between these cell lines in terms of the expressions of both a cluster of heat shock protein (HSP)-related genes and a cluster of apoptosis-related genes. Notably, inhibition of HSP90 in F28-7 cells caused a shift from the FUdR-induced necrosis into apoptosis. These findings are expected to lead to a better understanding of this anticancer drug FUdR for its molecular mechanisms and also of the general biological issue, necrosis and apoptosis.
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima, Okayama 700-8530, Japan.
Akira
A
Sato
Akiko
A
Hiramoto
Yusuke
Y
Uchikubo
Eriko
E
Miyazaki
Akito
A
Satake
Tomoharu
T
Naito
Osamu
O
Hiraoka
Tsuyoshi
T
Miyake
Hye-Sook
HS
Kim
Yusuke
Y
Wataya
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D005467:Floxuridine / Q000494:pharmacology*; D020869:Gene Expression Profiling; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009336:Necrosis / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis
D000964:Antimetabolites, Antineoplastic; D018841:HSP90 Heat-Shock Proteins; D005467:Floxuridine; D045304:Cytochromes c