Stimulation of protein kinase C-alpha suppresses colon cancer cell proliferation by down-regulation of beta-catenin.
We reported previously that protein kinase C-alpha (PKC-alpha) negatively regulates Wnt/beta-catenin signalling pathway. The current study explores the role of PKC-alpha in the regulation of proliferation of colon cancer cells, which contain aberrant up-regulation of intracellular beta-catenin. In colon tissue and cells, an inverse correlation was observed between the expression levels of PKC-alpha and intracellular beta-catenin. Activation of PKC-alpha inhibited beta-catenin response transcription by down-regulation of intracellular beta-catenin and induced phosphorylation of the N-terminal serine and threonine residues (Ser33/Ser37/Thr41) of beta-catenin, marking it for proteasomal degradation, in colon cancer cells. Pharmacological inhibition or depletion of PKC-alpha-abrogated PKC-alpha-mediated beta-catenin down-regulation and phosphorylation in colon cancer cells. Notably, the Ser45 residue of beta-catenin was essential for PKC-alpha-induced beta-catenin down-regulation in colon cancer cells. Moreover, PKC-alpha activation repressed the expression of cyclin D1 and c-myc, which are known beta-catenin target genes, and thus inhibited the growth of colon cancer cells. These findings suggest that PKC-alpha negatively regulates colon cancer cell proliferation viabeta-catenin phosphorylation/down-regulation and may facilitate the development of new strategies to treatment of colon cancer.
Gwak
Jungsug
J
PharmcoGenomics Research Center, Inje University, Busan, Korea.
Jung
Soo-Jin
SJ
Kang
Dong-Ii
DI
Kim
Eun-Young
EY
Kim
Dong-Eun
DE
Chung
Young-Hwa
YH
Shin
Jae-Gook
JG
Oh
Sangtaek
S
D001483:Base Sequence; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D017931:DNA Primers; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051176:beta Catenin / Q000378:metabolism*
D017931:DNA Primers; D051176:beta Catenin; D051571:Protein Kinase C-alpha