The basic and clinical implications of ABC transporters, Y-box-binding protein-1 (YB-1) and angiogenesis-related factors in human malignancies.
In our laboratories, we have been studying molecular targets which might be advantageous for novel cancer therapeutics. In this review, we focus on how ATP-binding cassette (ABC) transporter superfamily genes, Y-box-binding protein-1 (YB-1), and tumor angiogenesis-associated factors could contribute to the development of novel strategies for molecular cancer therapeutics. ABC transporters such as P-glycoprotein/MDR1 and several MRP family proteins function to protect cells from xenobiotics, drugs and poisons, suggesting that ABC transporters are a double-edged sword. In this regard, P-glycoprotein/MDR1 is a representative ABC transporter which plays a critical role in the efflux of a wide range of drugs. We have reported that gene amplification, gene rearrangements, transcription factor YB-1 and CpG methylation on the promoter are involved in MDR1 gene overexpression in cultured cancer cells. Among them, two mechanisms appear to be relevant to the up-regulation of MDR1 gene in human malignancies. We first reported that MDR1 gene promoter is activated in response to environmental stimuli, and is modulated by methylation/demethylation of CpG sites on the MDR1 promoter. We also demonstrated that YB-1 modulates not only transcription of various genes associated with cell growth, drug resistance and DNA synthesis, but also translation, mRNA stabilization and DNA repair/self-defense processes. Angiogenesis is also involved in tumor growth, invasion and metastasis of various malignancies, and so angiogenesis-related molecules also offer novel molecular targets for anticancer therapeutics.
Kuwano
Michihiko
M
Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582. kuwano@biochem1.med.kyushu-u.ac.jp
Uchiumi
Takeshi
T
Hayakawa
Hiroshi
H
Ono
Mayumi
M
Wada
Morimasa
M
Izumi
Hiroto
H
Kohno
Kimitoshi
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001692:Biological Transport; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016228:Endothelial Growth Factors / Q000502:physiology*; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008222:Lymphokines / Q000502:physiology*; D051839:NFI Transcription Factors; D009363:Neoplasm Proteins / Q000502:physiology*; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000503:physiopathology; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051840:Y-Box-Binding Protein 1
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D051839:NFI Transcription Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human