Defining targets of modulation of human tumor cell response to cisplatin.
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.
Beretta
Giovanni Luca
GL
Department of Experimental Oncology and Laboratories, Fondazione IRCCS, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milan, Italy.
Gatti
Laura
L
Corna
Elisabetta
E
Carenini
Nives
N
Zunino
Franco
F
Perego
Paola
P
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005978:Glutathione / Q000037:antagonists & inhibitors; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D061988:Proteasome Inhibitors
D006360:Heat-Shock Proteins; D061988:Proteasome Inhibitors; D005978:Glutathione; D002945:Cisplatin