HEF1 is a crucial mediator of the proliferative effects of prostaglandin E(2) on colon cancer cells.
Prostaglandin E(2) (PGE(2)), one of the downstream products of cyclooxygenase-2 enzymatic activity, promotes colorectal carcinogenesis in part by stimulating cell division. In this study, we define a critical mechanism in this process by showing that the prometastatic adapter protein human enhancer of filamentation 1 (HEF1; NEDD9) links PGE(2) to the cell cycle machinery in colorectal cancer cells. PGE(2) rapidly induced expression of HEF1 mRNA and protein in colorectal cancer cells. HEF1 overexpression elicited the same effects as PGE(2) treatment on cell proliferation, cell cycle progression, and tumor growth. Conversely, HEF1 knockdown suppressed PGE(2)-driven cell proliferation and cell cycle progression. Cell cycle alterations involved HEF1 fragmentation as well as co-distribution of HEF1 and cell cycle kinase Aurora A along spindle asters during cell division. Moreover, Aurora A co-immunoprecipitated with HEF1 and was activated by HEF1. Consistent with a role for HEF1 in colorectal carcinogenesis, we found elevated expression of HEF1 expression in 50% of human colorectal cancers examined, relative to paired normal tissues. These findings establish that PGE(2) induces HEF1 expression, which in turn promotes cell cycle progression through its interaction with and activation of Aurora A. Further, they establish that HEF1 is a crucial downstream mediator of PGE(2) action during colorectal carcinogenesis.
Xia
Dianren
D
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Holla
Vijaykumar R
VR
Wang
Dingzhi
D
Menter
David G
DG
DuBois
Raymond N
RN
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015232:Dinoprostone / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D015232:Dinoprostone