engleski

The role of RhoB in lovastatin-induced reversion of cisplatin resistance in human laryngeal carcinoma cells

Introduction: Acquired resistance to cisplatin represents a major obstacle to successful chemotherapy. Our cisplatin-resistant CA3ST and CK2 cells display cytoskeleton alterations comparing to parental human laryngeal carcinoma HEp-2 cells. Since lipid modification of Rho GTPases is essential for biological function, we analyzed their expression as well as the cellular response to HMG-CoA reductase inhibitor lovastatin. Methods: We used semiquantitative RT-PCR and Western blot analysis, transient transfection, flow cytometry and cytotoxicity assays. Results: Among several Rho GTPases analyzed, cisplatin-resistant cells displayed strong decrease of RhoB on both mRNA and protein level. Lovastatin treatment induced concentration-dependent increase in RhoB in all cell lines tested and cell cycle arrest in G1 phase, which was more pronounced in cisplatin-resistant than parental cells, whereas at later time points cisplatin-resistant cells were highly susceptible to apoptosis. This effect was suppressed by the addition of geranylgeranyl pyrophosphate, and to less extent farnesyl pyrophosphate. Furthermore, lovastatin pretreatment restored sensitivity of resistant cells to cisplatin to the level found in parental cells. In line with this, transient transfection of EGFP-RhoB in CA3ST cells restored their sensitivity to cisplatin. Conclusions: We conclude that in cisplatin-resistant and lovastatin-sensitive laryngeal carcinoma cells RhoB is involved in resistance to cisplatin. Moreover, since lovastatin has already entered clinical trials for several types of cancer, these data could lead to new clinical strategies aimed to overcome cisplatin resistance and improve efficacy of cancer treatment.

RhoB; cisplatin; drug-resistance; lovastatin

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