title: Oncogenic ras-induced down-regulation of pro-apoptotic protease caspase-2 is required for malignant transformation of intestinal epithelial cells.
abstract: Resistance of carcinoma cells to anoikis, apoptosis that is normally induced by loss of cell-to-extracellular matrix adhesion, is thought to be essential for the ability of these cells to form primary tumors, invade adjacent tissues, and metastasize to distant organs. Current knowledge about the mechanisms by which cancer cells evade anoikis is far from complete. In an effort to understand these mechanisms, we found that ras, a major oncogene, down-regulates protease caspase-2 (which initiates certain steps of the cellular apoptotic program) in malignant human and rat intestinal epithelial cells. This down-regulation could be reversed by inhibition of a protein kinase Mek, a mediator of Ras signaling. We also found that enforced down-regulation of caspase-2 in nonmalignant intestinal epithelial cells by RNA interference protected them from anoikis. Furthermore, the reversal of the effect of Ras on caspase-2 achieved by the expression of exogenous caspase-2 in detached ras-transformed intestinal epithelial cells promoted well established apoptotic events, such as the release of the pro-apoptotic mitochondrial factors cytochrome c and HtrA2/Omi into the cytoplasm of these cells, significantly enhanced their anoikis susceptibility, and blocked their long term growth in the absence of adhesion to the extracellular matrix. Finally, the blockade of the effect of Ras on caspase-2 substantially suppressed growth of tumors formed by the ras-transformed cells in mice. We conclude that ras-induced down-regulation of caspase-2 represents a novel mechanism by which oncogenic Ras protects malignant intestinal epithelial cells from anoikis, promotes their anchorage-independent growth, and allows them to form tumors in vivo.
authors: Department of Pediatrics, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada.
authors: Byong Hoon
authors: BH
authors: Yoo
authors: Yanfei
authors: Y
authors: Wang
authors: Mete
authors: M
authors: Erdogan
authors: Takehiko
authors: T
authors: Sasazuki
authors: Senji
authors: S
authors: Shirasawa
authors: Laurent
authors: L
authors: Corcos
authors: Kanaga
authors: K
authors: Sabapathy
authors: Kirill V
authors: KV
authors: Rosen
mesh_terms: D000818:Animals; D023102:Anoikis / Q000235:genetics; D053143:Caspase 2 / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D045304:Cytochromes c; D020930:MAP Kinase Kinase Kinases; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; C490360:CASP2 protein, human; C090208:Casp2 protein, mouse; C490359:Casp2 protein, rat; D053143:Caspase 2; D003546:Cysteine Endopeptidases; D018631:ras Proteins