Protein kinase C-alpha antagonizes apoptosis induction by histone deacetylase inhibitors in multidrug resistant leukaemia cells.
Previous studies have documented that while several drug-resistant cells enter apoptosis upon treatment with histone deacetylase inhibitors (iHDACs), their drug-sensitive counterparts do not. In the present study, we have investigated at the molecular level why parental drug-sensitive tumor cells do not respond to Trichostatin A and suberoylanilide hydroxamic acid, two iHDACs that promote apoptosis in drug-resistant leukaemia cells. Taking murine leukaemia L1210 cells as a model, we have determined that: (i) PKC-alpha expression is more elevated in parental L1210 than in drug-resistant L1210/R cells, (ii) activation of PKC neutralizes iHDACs-mediated apoptosis in L1210/R cells, (iii) depletion of PKC in parental L1210 cells results in a positive response to iHDACs-mediated apoptosis, and (iv) transfection of a mutant constitutively active PKC-alpha form in L1210/R cells makes the cells refractory to apoptosis induction by iHDACs. These results allow us to conclude that activation/high expression of PKC-alpha protects parental drug-sensitive L1210 cells from iHDACs-mediated apoptosis. Thus, determination of PKC-alpha levels/activity in leukaemia seems to be relevant when choosing efficient chemotherapy protocols based on the use of apoptosis-inducing anticancer drugs.
Castro-Galache
María D
MD
Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, Avda. de la Universidad s/n., 03202 Elche, Alicante, Spain.
Menéndez-Gutiérrez
Maria P
MP
Carrasco Garcia
Estefania
E
Garcia-Morales
Pilar
P
Martinez-Lacaci
Isabel
I
Saceda
Miguel
M
Ferragut
Jose A
JA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D000077337:Vorinostat
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050505:Mutant Proteins; C012589:trichostatin A; D000077337:Vorinostat; D051571:Protein Kinase C-alpha