Defining targets of modulation of human tumor cell response to cisplatin

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• 作者：Giovanni Luca Beretta ; Laura Gatti ; Elisabetta Corna ; Nives Carenini ; Franco Zunino ; Paola Perego
• 关键词：Cisplatin ; Human tumor cells ; Resistance ; Modulation ; Stress response
• 刊名：Journal of Inorganic Biochemistry
• 出版年：2008
• 出版时间：July 2008
• 年：2008
• 卷：102
• 期：7
• 页码：1406-1415
• 全文大小：764 K

文摘

We previously observed that in yeast cisplatin activates different pathways accounting for stress response. Here, we investigated whether genes involved in yeast drug response were modulated by cisplatin in human tumor cell lines (A2780, IGROV-1, A431, U2-OS) including cisplatin-resistant sublines (A2780/BBR, IGROV-1/Pt1, A431/Pt and U2-OS/Pt). Factors and pathways involved in stress response (glutathione-S-transferase, proteasome, checkpoint control and recombinational repair) were increased by cisplatin in human tumor sensitive and resistant cells. Moreover, sensitization to cisplatin by pharmacologically targeting glutathione or proteasome was observed in sensitive and resistant cells. Interestingly, only in IGROV-1/Pt1 cells, in which cisplatin up-regulated HSP70 and HSP90, targeting of HSP90 resulted in sensitization of resistant cells, suggesting a protective role of stress response. In conclusion, the present findings support the potential relevance of interfering with heat shock protein response to increase cisplatin cytotoxicity in resistant cells. Overall, pathways activated by cisplatin in human tumor cells appear cell-type specific, at least in part reflecting the stress response observed in yeast.