Gene expression profiles of necrosis and apoptosis induced by 5-fluoro-2′-deoxyuridine

Abstract

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.

Protein Expression Profiles of Necrosis and Apoptosis Induced by 5-Fluoro-2′-deoxyuridine in Mouse Cancer Cells

“…6 Reports from other laboratories have shown that mitochondria play a role in mediating both necrosis and apoptosis. [25][26][27] Interestingly, a number of the mitochondrial proteins exhibit differential expressions in F28-7 and F28-7-A cells either in the untreated stages or in the FUdR-treated stages.…”

“…5,6 FUdR, a potent anticancer agent, exerts its effect by inhibiting thymidylate synthase, an essential machinery for DNA synthesis in cell proliferation (see ref 7 and references therein). Previously, we reported that the treatment can induce in F28-7 cells a breakdown of DNA into chromosome-sized fragments leading to necrosis, and that it can induce in F28-7-A more extensive DNA cleavage into oligonucleosome-sized fragments and subsequent development of apoptosis.…”

Aquatic birnavirus capsid protein, VP3, induces apoptosis via the Bad-mediated mitochondria pathway in fish and mouse cells

“…Recently, Sato et al [49] determined the gene expression profile induced by an anticancer agent, 5-fluoro-2 0 -deoxyuridine (FUdR), in mouse mammary FM3A tumors to elucidate the molecular mechanisms regulating necrosis. In another example, TNFa activated RIP 1 kinase-mediated signaling for the induction of downstream genes influencing necrosis or apoptosis, as revealed by Hitom et al [50].…”

RGNNV induces mitochondria-mediated cell death via newly synthesized protein dependent pathway in fish cells

“…Recently, investigating the molecular mechanisms regulating necrosis, Sato et al [43] identified the gene expression profile induced by an anticancer agent, 5-fluoro-2 0 -deoxyuridine (FUdR), in mouse mammary FM3A tumors, which required gene expression for triggering their necrosis [43]. On the other hand, TNF a activates the RIP 1 kinase-mediated signaling for the induction of downstream genes influencing necrosis or apoptosis [44,45].…”