Molecular alterations of cells resistant to platinum drugs: role of PKCalpha.
Development of resistance to platinum compounds may involve not only overexpression of defence mechanisms but also alterations in cellular response to the drug-induced genotoxic stress. To investigate the cellular bases of response to platinum compounds, we examined the profile of gene expression of ovarian carcinoma cells exhibiting sensitivity (A2780) or resistance (A2780/BBR3464) to platinum compounds. Using display PCR, we found that acquisition of resistance to the multinuclear platinum complex BBR3464 was associated with modulation of several transcripts, including up-regulation of the major substrate of protein kinase C (PKC), the myristoylated alanine-rich C kinase substrate (MARCKS). This feature was associated with PKCalpha down-regulation. To explore the role of PKCalpha in cellular sensitivity to platinum compounds, resistant cells were transfected with a PKCalpha-containing vector. PKCalpha-overexpressing resistant cells exhibited a decrease in sensitivity to cisplatin, whereas no significant change in sensitivity to BBR3464 was observed. A number of approaches designed to modulate the function or expression of PKCalpha support that the isoenzyme may play a role in determining resistance only to cisplatin but not to BBR3464, which is known to activate a different pathway of cell response. In conclusion, in spite of PKCalpha down-regulation in our model, its regulatory function was not apparently implicated in the development of resistance to platinum compounds and the present results do not support a general role of PKCalpha as a determinant of the resistance status.
Istituto Nazionale per lo Studio e la Cura dei Tumori, via Venezian 1, 20133 Milan, Italy.
Sabina C
SC
Righetti
Paola
P
Perego
Nives
N
Carenini
Elisabetta
E
Corna
Laura
L
Dal Bo
Sabrina
S
Cedrola
Caterina A M
CA
La Porta
Franco
F
Zunino
D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010641:Phenotype; D017671:Platinum Compounds / Q000494:pharmacology*; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D015203:Reproducibility of Results; D014162:Transfection
D004338:Drug Combinations; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; C000619710:MARCKS protein, human; D008565:Membrane Proteins; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D051571:Protein Kinase C-alpha; C114062:BBR 3464; D002945:Cisplatin