Distinct protein kinase C isozymes signal mitogenesis and apoptosis in human colon cancer cells.
OBJECTIVE
Protein kinase C (PKC) is a family of serine-threonine kinases that transmit signals from cell surface receptors. To determine if distinct PKC isozymes transmit proliferative and/or apoptotic signals in colon cancer cells, we examined the effects of 3 PKC agonists, phorbol 12-myristate 13 acetate (PMA), ingenol 3,20-dibenzoate (IDB), and bistratene A, and a selective PKC inhibitor, GF 109203X, on proliferation, apoptosis, and activation of individual PKC isozymes in 5 colon cancer cell lines.


METHODS
Effects were assayed by a formazan-based colorimetric assay, [(3)H]thymidine incorporation, fluorescent nuclear staining, annexin V binding, DNA fragmentation assay, and immunoblotting of cytoplasmic and membrane fractions for PKC isozymes.


RESULTS
Two cell lines, SNU-C1 and SNU-C4, showed proliferative responses to PMA (0.1-1 nmol/L) and IDB (10-1000 nmol/L) and marked apoptotic responses to PMA (>5 nmol/L) and bistratene A (>1 micromol/L). GF 109203X blocked proliferative and apoptotic effects of PMA with distinct IC(50)s. Proliferative concentrations of PMA and IDB caused translocation of PKCepsilon alone, whereas apoptotic concentrations of PMA and bistratene A induced translocation of PKCdelta.


CONCLUSIONS
Activation of PKCepsilon and PKCdelta triggers proliferative and apoptotic signals, respectively, in SNU-C4 colon cancer cells. These 2 isozymes may play important opposing roles in normal homeostasis and neoplastic transformation of the colorectal epithelium.
Weller
S G
SG
Colorectal Neoplasia Group, Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA.
Klein
I K
IK
Penington
R C
RC
Karnes
W E
WE
D000081:Acetamides; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001692:Biological Transport / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D015179:Colorectal Neoplasms / Q000473:pathology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000187:drug effects / Q000502:physiology*; D008301:Maleimides / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D009994:Osmolar Concentration; D011493:Protein Kinase C / Q000187:drug effects / Q000502:physiology*; D011714:Pyrans; D015398:Signal Transduction / Q000502:physiology*; D013141:Spiro Compounds; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000081:Acetamides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004988:Ethers, Cyclic; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D011714:Pyrans; D013141:Spiro Compounds; C059975:bistratene A; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate