Oncogenic K-RAS is required to maintain changes in cytoskeletal organization, adhesion, and motility in colon cancer cells.
RAS oncogenes are thought to play a role at multiple stages of tumorigenesis. The role and mechanisms by which RAS oncogenes maintain the transformed state of human cancer cells are poorly understood. Here, we have studied the role of oncogenic K-RAS in maintaining cytoskeletal disruption, cell adhesion and motility in metastatic colon carcinoma cells. Targeted deletion of K-RAS(G13D) from HCT116 colon carcinoma cells restored their ability to assemble stress fibers and focal adhesions/complexes, accompanied by increased cell-matrix adhesion and reduced motility. We further show that oncogenic K-Ras induces high Rho activity, but uncouples Rho from stress fiber formation. This uncoupling required the maintenance of high levels of the activator protein-1 family member, Fra-1, via a mitogen-activated protein/extracellular signal-regulated kinase-dependent pathway. We also show that PI3-kinase signaling is required for the motility of HCT116 cells downstream of oncogenic K-Ras. Our findings suggest that mutated K-RAS oncogenes are essential for maintenance of the transformed and invasive phenotype of human colon cancer cells.
Pollock
Claire B
CB
The Beatson Institute for Cancer Research, Garscube Estate, Bearsden, United Kingdom.
Shirasawa
Senji
S
Sasazuki
Takehiko
T
Kolch
Walter
W
Dhillon
Amardeep S
AS
D000199:Actins / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D003599:Cytoskeleton / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D017353:Gene Deletion; D011905:Genes, ras / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D014162:Transfection; D000099169:Fos-Related Antigen 1
D000199:Actins; D020930:MAP Kinase Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D016760:Proto-Oncogene Proteins c-fos; D000099169:Fos-Related Antigen 1