title: Insight into the 6-thiopurine-mediated termination of the invasive motility of tumor cells derived from inflammatory breast cancer.
abstract: Our study showed that a combination of 6-thiopurine (6-TP) drugs and a redox agent effectively inhibits the motility of SUM cells derived from human inflammatory breast cancer (IBC) cells and RhoC-overexpressed mammary epithelium cells. This 6-TP-mediated inhibition of cell motility occurs because the treated 6-TPs target and inactivate RhoC. A molecular mechanism for inactivation by the 6-TP-mediated RhoC is proposed by which treated TPs are converted in cells into 6-thioguanosine phosphate (6-TGNP). This 6-TGNP in turn reacts with the Cys(20) side chain of the redox-sensitive GXXXCGK(S/T)C motif of RhoC to produce a 6-TGNP-RhoC disulfide adduct. A redox agent synergistically enhances the formation process of this disulfide. The adduct that is formed impedes RhoC guanine nucleotide exchange, which populates an inactive RhoC. Our results suggest that 6-TGNP can also react with the redox-sensitive GXXXCGK(S/T)C and GXXXXGK(S/T)C motif of RhoA and Rac, respectively, to produce a 6-TGNP-RhoA and 6-TGNP-Rac disulfide adduct. However, given that RhoC has been shown to be overexpressed in ∼90% of IBC lesions, the populated RhoC but not other Rho proteins is likely to be a primary target for 6-TPs and a redox agent to terminate the metastasis of IBC.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, Texas 76019, USA. jheo@uta.edu
authors.forename: Jongyun
authors.initials: J
authors.lastname: Heo
authors.forename: Michael
authors.initials: M
authors.lastname: Wey
authors.forename: Inpyo
authors.initials: I
authors.lastname: Hong
mesh_terms: D001943:Breast Neoplasms / Q000737:chemistry / Q000473:pathology* / Q000628:therapy*; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition / Q000187:drug effects* / Q000502:physiology; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems / Q000379:methods; D004357:Drug Synergism; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D006150:Guanine Nucleotides; D006801:Humans; D018836:Inflammation Mediators / Q000737:chemistry* / Q000627:therapeutic use*; D015122:Mercaptopurine / Q000737:chemistry* / Q000627:therapeutic use*; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D010084:Oxidation-Reduction / Q000187:drug effects; D011355:Prodrugs / Q000737:chemistry / Q000627:therapeutic use; D013873:Thionucleotides; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000075024:rhoC GTP-Binding Protein
chemical_list: D006150:Guanine Nucleotides; D018836:Inflammation Mediators; D011355:Prodrugs; D013873:Thionucleotides; C003964:6-thioguanylic acid; D015122:Mercaptopurine; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein