Down-regulation of mitochondrial gene expression by the anti-tumor arotinoid mofarotene (Ro 40-8757).

Abstract

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.

• Authors: T Uchida, N Inagaki, Y Furuichi, J F Eliason
• Journal: International journal of cancer (Int J Cancer) Vol. 58 Issue 6 Pg. 891-7 (Sep 15 1994) ISSN: 0020-7136 [Print] United States
• PMID: 7927884 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• DNA Probes
• DNA, Mitochondrial
• DNA, Neoplasm
• Morpholines
• Retinoids
• mofarotene
• NADH Dehydrogenase

Topics

• Antineoplastic Agents (pharmacology)
• Base Sequence
• Blotting, Northern
• Cell Division (drug effects, physiology)
• DNA Probes
• DNA, Mitochondrial (genetics)
• DNA, Neoplasm (genetics)
• Down-Regulation (drug effects)
• Gene Expression (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Genome, Human
• Humans
• Kinetics
• Mitochondria (drug effects, physiology)
• Molecular Sequence Data
• Morpholines (pharmacology)
• NADH Dehydrogenase (genetics)
• Neoplasms (genetics)
• Retinoids (pharmacology)
• Tumor Cells, Cultured