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2014 ; 53 Suppl 1
(0 1
): E169-80
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Reg4-induced mitogenesis involves Akt-GSK3?-?-Catenin-TCF-4 signaling in human
colorectal cancer
#MMPMID24151146
Bishnupuri KS
; Sainathan SK
; Bishnupuri K
; Leahy DR
; Luo Q
; Anant S
; Houchen CW
; Dieckgraefe BK
Mol Carcinog
2014[Feb]; 53 Suppl 1
(0 1
): E169-80
PMID24151146
show ga
Upregulation of regenerating gene 4 (Reg4) is observed in many human
gastrointestinal malignancies including colorectal cancer (CRC). We previously
reported a Reg4-mediated induction of epidermal growth factor receptor-Akt-AP1
signaling regulating CRC cell apoptosis. However, the role of Reg4 in the
regulation of CRC cell division is poorly understood. This study tests the
hypothesis that Reg4 induces Akt-GSK3?-?-Catenin-TCF-4 signaling to regulate CRC
cell division. In vitro models of human CRC were used to determine the role of
Reg4 in regulation of CRC cell division. Cell cycle studies demonstrated that
Reg4 treatment significantly decreased CRC cell number in G1 phase and increased
in G2 phase. Subsequently Reg4 significantly increased the mitotic index of CRC
cells. As assessed by real-time RT-PCR and Western blot analyses, Reg4
significantly increased the expression of cell cycle regulatory genes Cyclin D1
and D3, and associated Cyclin-dependent kinases (CDK4 and CDK6). Reg4-mediated
increase in these genes involved a pathway that included an induced Akt activity
by increasing phosphorylation of Thr308 and Ser473, a reduced glycogen synthase
kinase 3? (GSK-3?) activity by increasing phosphorylation of Ser9, an induced
nuclear translocation of ?-Catenin by decreasing phosphorylation of
Ser33/37/Thr41, and an increased TCF-4 transcriptional activity. Furthermore,
antagonism of Reg4-signaling using Reg4-specific mAbs (2H6 and 3E5) and Akt
inhibitor significantly decreased, whereas agonism using GSK-3? antagonist
(SB216763) significantly increased mitotic index and proliferation of CRC cells.
These results identify Reg4 as a key regulator of the CRC cell division and
proliferation, hence a potential target of human CRC treatment.