Focal adhesion kinase as a therapeutic target of bortezomib.
Bortezomib, a modified dipeptidyl boronic acid, is a selective potent proteasome inhibitor that has been approved for clinical treatment of multiple myeloma and mantel cell lymphoma. Results from a growing number of basic studies and clinical trials reveal that bortezomib could be used to treat diverse types of solid tumors alone or in combination with other chemotherapeutic drugs. It has been shown that bortezomib transcriptionally suppresses focal adhesion kinase (FAK) expression by interrupting the nuclear factor kappa B (NFκB) pathway, which suggests that FAK could be a potential molecular target for bortezomib. Analysis of FAK promoter sequences revealed that FAK promoter harbors the NFκB and p53 binding domains. Further studies of FAK promoter activity, real-time PCR, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay revealed that bortezomib inhibits NFκB binding on the FAK promoter, thereby reducing FAK expression. Thus, bortezomib could inhibit cancer cell growth and migration or invasion by repressing FAK expression. Since activation and overexpression of FAK has been implicated in the progression and invasion of malignant tumors, it is likely that targeting FAK with bortezomib is a potential strategy for preventing cancer metastasis. This review focuses on the molecular regulation of FAK and the potential clinical application of bortezomib.
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
Bor-Sheng
BS
Ko
Tzu-Ching
TC
Chang
Jun-Yang
JY
Liou
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D051416:Focal Adhesion Protein-Tyrosine Kinases