Expression of protein kinase C beta1 confers resistance to TNFalpha- and paclitaxel-induced apoptosis in HT-29 colon carcinoma cells.
The expression of different protein kinase C (PKC) isoenzymes has been shown to vary with proliferation rates, differentiation or apoptosis in normal colon crypts. In addition, the activity of some PKC isoenzymes appears to be reduced in colorectal cancer. The aim of the present work was to determine whether modulation of PKC expression would affect the susceptibility of a p53-defective colon carcinoma cell line to different apoptotic treatments. HT-29 cells exhibited sensitivity to paclitaxel (Taxol) and tumor necrosis factor alpha (TNFalpha) in a dose- and time-dependent manner but were relatively resistant to etoposide. Inhibition of PKC activity augmented the susceptibility of HT-29 cells to apoptosis, and phorbol ester induction of PKC reduced such susceptibility. Transfected HT-29(PKC) cells, hyper-expressing the beta1 isoform of PKC, were less sensitive to TNFalpha and paclitaxel than the normal counterpart. The present data 1) indicate that the expression of PKC influences the susceptibility of HT-29 colon cancer cells to apoptotic drugs apparently regardless of their mechanism of action, and 2) suggest paclitaxel as a potential candidate for the treatment of colon cancer, possibly in association with inhibitors of PKC (alpha and beta) at doses not cytotoxic per se.
Cesaro
P
P
Dipartimento di Scienze Mediche, Università A. Avogadro, Via Solaroli 17, 28100 Novara, Italy.
Raiteri
E
E
Démoz
M
M
Castino
R
R
Baccino
F M
FM
Bonelli
G
G
Isidoro
C
C
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000502:physiology; D017239:Paclitaxel / Q000008:administration & dosage; D011493:Protein Kinase C / Q000096:biosynthesis* / Q000502:physiology; D064546:Protein Kinase C beta; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
D007527:Isoenzymes; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D017239:Paclitaxel