title: PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer.
abstract: Reduced expression of both classical and desmosomal cadherins has been associated with different types of carcinomas, including prostate cancer. This study aims to provide a comprehensive view of the role and regulation of cell-cell adhesion in prostate cancer aggressiveness by examining the functional implications of both E-cadherin and Desmoglein 2 (DSG2). E-cadherin expression was first examined using immunofluorescence in 50 normal prostate tissues and in a cohort of 414 prostate cancer patients. Correlation and survival analyses were performed to assess its clinical significance. In primary prostate cancer patients, reduced expression of both E-cadherin and DSG2 is significantly associated with an earlier biochemical recurrence. Transgenic DU145 E-cadherin knockdown and constitutively active AKT overexpression lines were generated. Functional implications of such genetic alterations were analyzed in vitro and in vivo, the latter by using tumorigenesis as well as extravasation and metastatic tumor formation assays. We observed that loss of E-cadherin leads to impaired primary and metastatic tumor formation in vivo, suggesting a tumor promoter role for E-cadherin in addition to its known role as a tumor suppressor. Activation of AKT leads to a significant reduction in E-cadherin expression and nuclear localization of Snail, suggesting a role for the PI3K/AKT signaling pathway in the transient repression of E-cadherin. This reduced expression may be regulated by separate mechanisms as neither the loss of E-cadherin nor activation of AKT significantly affected DSG2 expression. In conclusion, these findings illustrate the critical role of cell-cell adhesion in the progression to aggressive prostate cancer, through regulation by the PI3K pathway.
authors.affiliation: Department of Genetics and Development, Columbia University, New York City, New York.
authors.forename: Alison G
authors.initials: AG
authors.lastname: Barber
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York City, New York.
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo-Martin
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York City, New York.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Bonal
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York City, New York.|Herbert Irving Comprehensive Cancer Center, Columbia University, New York City, New York.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Jia
authors.affiliation: Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Rybicki
authors.affiliation: Department of Genetics and Development, Columbia University, New York City, New York.|Department of Dermatology, Columbia University, New York City, New York.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Christiano
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York City, New York.|Herbert Irving Comprehensive Cancer Center, Columbia University, New York City, New York.|Department of Pathology and Cell Biology, Columbia University, New York City, New York.|Department of Urology, Columbia University, New York City, New York.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor; D015820:Cadherins / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D051301:Desmoglein 2 / Q000235:genetics*; D003896:Desmosomes / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D051301:Desmoglein 2; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Desmoglein 2; E-cadherin; PI3K/AKT pathway; prognostic markers; prostate cancer