title: Role of Akt2 in regulation of metastasis suppressor 1 expression and colorectal cancer metastasis.
abstract: Survival signaling is critical for the metastatic program of cancer cells. The current study investigated the role of Akt survival proteins in colorectal cancer (CRC) metastasis and explored potential mechanisms of Akt-mediated metastasis regulation. Using an orthotopic implantation model in mice, which uniquely recapitulates the entire multistep process of CRC metastasis, combined with an inducible system of short hairpin RNA-mediated Akt isoform knockdown in human CRC cells, our studies confirm a role of Akt2 in CRC cell dissemination to distant organs in vivo. Akt2 deficiency profoundly inhibited the development of liver lesions in mice, whereas Akt1 had no effect under the experimental conditions used in the study. Array analysis of human metastatic genes identified the scaffolding protein metastasis suppressor 1 (MTSS1) as a novel Akt2-regulated gene. Inducible loss of Akt2 in CRC cells robustly upregulated MTSS1 at the messenger RNA and protein level, and the accumulated protein was functionally active as shown by its ability to engage an MTSS1-Src-cortactin inhibitory axis. MTSS1 expression led to a marked reduction in levels of functional cortacin (pcortactin Y421), an actin nucleation-promoting factor that has a crucial role in cancer cell invasion and metastasis. MTSS1 was also shown to mediate suppressive effects of Akt2 deficiency on CRC cell viability, survival, migration and actin polymerization in vitro. The relevance of these findings to human CRC is supported by analysis of The Cancer Genome Atlas (TCGA) and NCBI GEO data sets, which demonstrated inverse changes in expression of Akt2 and MTSS1 during CRC progression. Taken together, the data identify MTSS1 as a new Akt2-regulated gene, and point to suppression of MTSS1 as a key step in the metastasis-promoting effects of Akt2 in CRC cells.
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska, USA.|Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: E
authors.initials: E
authors.lastname: Agarwal
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Robb
authors.affiliation: Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Smith
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska, USA.|Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Brattain
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Black
authors.affiliation: Department of Medicine, Section of Gastroenterology, Boston University Medical Center, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chowdhury
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000096:biosynthesis* / Q000235:genetics; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*
chemical_list: C486778:MTSS1 protein, human; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt