Lysophosphatidic acid facilitates proliferation of colon cancer cells via induction of Krüppel-like factor 5.
Among the multiple cellular effects mediated by lysophosphatidic acid (LPA), the effect on cell proliferation has extensively been investigated. A recent study showed that LPA-mediated proliferation of colon cancer cells requires activation of beta-catenin. However, the majority of colon cancer cells have deregulation of the Wnt/beta-catenin pathway. This prompted us to hypothesize the presence of additional pathway(s) activated by LPA resulting in an increase in the proliferation of colon cancer cells. Krüppel-like factor 5 (KLF5) is a transcriptional factor highly expressed in the crypt compartment of the intestinal epithelium. In this work, we investigated a role of KLF5 in LPA-mediated proliferation. We show that LPA stimulated the expression levels of KLF5 mRNA and protein in colon cancer cells and this stimulation was mediated by LPA(2) and LPA(3). Silencing of KLF5 expression by small interfering RNA significantly attenuated LPA-mediated proliferation of SW480 and HCT116 cells. LPA-mediated KLF5 induction was partially blocked by inhibition of the mitogen-activated protein kinase kinase and protein kinase C-delta. Moreover, we observed that LPA regulates KLF5 expression via eukaryotic elongation factor 2 kinase (eEF2k). Inhibition of calmodulin or silencing of eEF2k blocked the stimulation in KLF5 expression. Knockdown of eEF2k specifically inhibited KLF5 induction by LPA but not by fetal bovine serum or phorbol 12-myristate 13-acetate. These results identify KLF5 as a target of LPA-mediated signaling and suggest a role of KLF5 in promoting proliferation of intestinal epithelia in response to LPA.
Zhang
Huanchun
H
Division of Digestive Diseases, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Bialkowska
Agnieszka
A
Rusovici
Raluca
R
Chanchevalap
Sengthong
S
Shim
Hyunsuk
H
Katz
Jonathan P
JP
Yang
Vincent W
VW
Yun
C Chris
CC
D018938:Caco-2 Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054736:Elongation Factor 2 Kinase; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis*; D008246:Lysophospholipids / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D002147:Calmodulin; D002273:Carcinogens; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D008246:Lysophospholipids; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin; C517689:EEF2K protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D054736:Elongation Factor 2 Kinase; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate