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.