engleski

Cytoskeleton alterations in cisplatin-resistant cells: The role of Rho GTPases in cisplatin toxicity

Acquired resistance to cisplatin represents a major obstacle to successful chemotherapy. We have developed cisplatin-resistant CA3ST cells, which exhibited pronounced stress fibers and numerous focal contacts, in contrast to parental human laryngeal carcinoma HEp-2 cells that displayed cortical actin organized in adhesion belt and few vinculin-containing focal adhesions. In line with these cytoskeleton alterations, CA3ST cells had increased expression of RhoA GTPase, on both protein and mRNA level, while the expression of Rac1 was unchanged comparing to HEp-2 cells. A single cisplatin treatment of HEp-2 cells induced formation of stress fibers and vinculin relocalization to focal contacts, which was preceded by translocation of RhoA, but not Rac1, to the cell membrane. Pretreatment with lovastatin decreased the level of membrane-bound RhoA, leading to increased fraction of apoptotic cells after cisplatin treatment. Moreover, since CA3ST cells were more sensitive than HEp-2 cells to lovastatin-induced apoptosis, lovastatin pretreatment restored sensitivity of resistant cells to cisplatin to the level found in parental cells. In addition, cisplatin-resistant human cervical carcinoma cells also showed increased RhoA protein and mRNA. Therefore, we speculate that upregulation of RhoA GTPase could be a general phenomena accompanying cisplatin resistance and might be involved in cellular response to cisplatin.

cisplatin; cytoskeleton; Rho GTPase

nije evidentirano