title: Diverse effects of ANXA7 and p53 on LNCaP prostate cancer cells are associated with regulation of SGK1 transcription and phosphorylation of the SGK1 target FOXO3A.
abstract: Tumor suppressor function of the calcium/phospholipid-binding Annexin-A7 (ANXA7) has been shown in Anxa7-deficient mice and validated in human cancers. In the androgen-resistant prostate cancer cells, ANXA7 and p53 showed similar cytotoxicity levels. However, in the androgen-sensitive LNCaP, ANXA7 greatly exceeded the p53-induced cytotoxicity. We hypothesized that the p53 underperformance in LNCaP could be due to the involvement of p53-responsive SGK1 and FOXO3A. In this study, we show that p53 failed to match programmed cell death (PCD) and G1-arrest that were induced by ANXA7 in LNCaP. WT-ANXA7 preserved total FOXO3A expression with no hyperphosphorylation that could enable FOXO3A nuclear translocation and proapoptotic transcription. In contrast, in the p53-transfected LNCaP cells with maintained cell proliferation, the phosphorylated (but not total) FOXO3A fraction was increased implying a predominantly cytoplasmic localization and, subsequently, a lack of FOXO3A proapoptotic transcription. In addition, p53 reduced the expression of aberrant SGK1 protein form in LNCaP. Using Ingenuity Pathway Analysis and p53-signature genes, we elucidated the role of distinct SGK1/FOXO3A-associated regulation in p53 versus ANXA7 responses and proposed that aberrant SGK1 could affect reciprocal SGK1-FOXO3A-Akt regulation. Thus, the failure of the cell growth regulator p53 versus the phospholipid-binding ANXA7 could be potentially attributed to its diverse effects on SGK1-FOXO3A-Akt pathway in the PTEN-deficient LNCaP.
authors.affiliation: Department of Anatomy, Physiology and Genetics and Institute for Molecular Medicine, Uniformed Services University of Health Sciences (USUHS), School of Medicine, Bethesda, MD 20814, USA.
authors.forename: Meera
authors.identifier: 0000-0002-8447-1330
authors.initials: M
authors.lastname: Srivastava
authors.affiliation: Department of Anatomy, Physiology and Genetics and Institute for Molecular Medicine, Uniformed Services University of Health Sciences (USUHS), School of Medicine, Bethesda, MD 20814, USA.
authors.forename: Ximena
authors.identifier: 0000-0003-1681-7771
authors.initials: X
authors.lastname: Leighton
authors.affiliation: Department of Anatomy, Physiology and Genetics and Institute for Molecular Medicine, Uniformed Services University of Health Sciences (USUHS), School of Medicine, Bethesda, MD 20814, USA.
authors.forename: Joshua
authors.identifier: 0000-0003-3097-3084
authors.initials: J
authors.lastname: Starr
authors.affiliation: Department of Anatomy, Physiology and Genetics and Institute for Molecular Medicine, Uniformed Services University of Health Sciences (USUHS), School of Medicine, Bethesda, MD 20814, USA.
authors.forename: Ofer
authors.identifier: 0000-0001-5111-0371
authors.initials: O
authors.lastname: Eidelman
authors.affiliation: Department of Anatomy, Physiology and Genetics and Institute for Molecular Medicine, Uniformed Services University of Health Sciences (USUHS), School of Medicine, Bethesda, MD 20814, USA.
authors.forename: Harvey B
authors.initials: HB
authors.lastname: Pollard
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D017310:Annexin A7 / Q000378:metabolism*; D001483:Base Sequence; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D014176:Protein Biosynthesis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000728:Androgens; D017310:Annexin A7; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D017874:Immediate-Early Proteins; D007527:Isoenzymes; D017346:Protein Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D000099184:Serum-Glucocorticoid Regulated Kinases; C499517:FOXO3 protein, human