Down-regulation of mitochondrial gene expression by the anti-tumor arotinoid mofarotene (Ro 40-8757).
To understand the mechanism of action of the antitumor arotinoid mofarotene (Ro 40-8757), differential screening of cDNA libraries with cDNA probes prepared from treated or untreated breast-cancer cells was performed. Several genes were identified that appeared to be regulated by mofarotene, including a mitochondrial gene encoding a subunit of NADH dehydrogenase (NDI). This gene was down-regulated in the breast-cancer cell line MDA-MB-231 after treatment with the arotinoid for 3 to 6 hr. Down-regulation of NDI was detected in 2 other breast-carcinoma cell lines (ZR-75-I and MCF-7) and a pancreatic cancer cell line (BxPC3), but not in the normal fibroblast cell line Wi-38 or several other tumor cell lines. This effect was blocked by addition of cycloheximide to the medium. The retinoids, all-trans and 9-cis retinoic acids, did not affect the expression of NDI in MDA-MB-231 cells, demonstrating that mofarotene was not acting through the nuclear retinoic-acid receptors. In the estrogen-receptor-expressing breast-cancer line ZR-75-I, tamoxifen had no effect on NDI expression. The cytotoxic drugs doxorubicin, 5-FU and vincristine also had no effect on regulation of this gene. Two mitochondrial proteins encoded in the nucleus, ATPase beta subunit and mitochondrial transcription factor I, were not down-regulated by mofarotene. Addition of mofarotene to cells incubated in glucose-free medium led to their death. These results indicate that down-regulation of mitochondrial gene transcription is specific to mofarotene and may explain, in part, the anti-proliferative effects of this compound.
Uchida
T
T
Department of Oncology, Nippon Roche Research Center, Kanagawa Prefecture, Japan.
Inagaki
N
N
Furuichi
Y
Y
Eliason
J F
JF
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D015342:DNA Probes; D004272:DNA, Mitochondrial / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D015894:Genome, Human; D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology*; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology*; D009245:NADH Dehydrogenase / Q000235:genetics; D009369:Neoplasms / Q000235:genetics; D012176:Retinoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D015342:DNA Probes; D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm; D009025:Morpholines; D012176:Retinoids; C081137:mofarotene; D009245:NADH Dehydrogenase