Kallikrein 6 is a mediator of K-RAS-dependent migration of colon carcinoma cells.
Kallikrein 6 (KLK6) is a trypsin-like serine peptidase whose relevance in various types of cancers is currently being explored. Previous studies have shown that KLK6 mRNA is upregulated in colon and gastric cancers; however, the regulatory mechanisms and phenotypic consequences of this upregulation are largely unknown. Activating K-RAS mutations are common in colon cancer, occurring in approximately 50% of cases. We have recently reported the upregulation of KLK6 mRNA in Caco2 human colon cancer cells stably transfected with a mutant K-RAS allele (K-RAS(G12V)). In this study we examined the pattern of K-RAS-dependent KLK6 expression and secretion in colon cancer cells. Using pharmacological inhibitors of pathways downstream of K-RAS, we could show that the PI3K and p42/44 MAPK pathways play an important role in the induction of KLK6 in mutant K-RAS-expressing colon cancer cells. Increased KLK6 expression enhanced colon cancer cell migration through laminin and Matrigel. Inhibition of KLK6 using small interference RNA treatment or a specific KLK6 antibody in Caco2 cells stably expressing the mutant K-RAS and in SW480 cells carrying a mutation in the K-RAS oncogene resulted in a reduction in invasiveness through cell culture inserts. These data support the oncogenic role of KLK6 in colorectal cancer.
Henkhaus
Rebecca S
RS
Cancer Biology Interdisciplinary Program, Arizona Cancer Center, The University of Arizona, 1515 N. Campbell Ave., Tucson, AZ 85724, USA.
Gerner
Eugene W
EW
Ignatenko
Natalia A
NA
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen; D003110:Colonic Neoplasms / Q000473:pathology*; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D007610:Kallikreins / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011509:Proteoglycans; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007074:Immunoglobulin G; D007797:Laminin; D011509:Proteoglycans; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C059485:matrigel; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C103551:KLK6 protein, human; D007610:Kallikreins; D016283:Proto-Oncogene Proteins p21(ras)