title: CCN5/WISP-2 promotes growth arrest of triple-negative breast cancer cells through accumulation and trafficking of p27(Kip1) via Skp2 and FOXO3a regulation.
abstract: The matricellular protein CCN5/WISP-2 represents a promising target in triple-negative breast cancer (TNBC) because treatment or induced activation of CCN5 in TNBC cells promotes cell growth arrest at the G0/G1 phase, reduces cell proliferation and delays tumor growth in the xenograft model. Our studies found that the p27(Kip1) tumor suppressor protein is upregulated and relocalized to the nucleus from cytoplasm by CCN5 in these cells and that these two events (upregulation and relocalization of p27(Kip1)) are critical for CCN5-induced growth inhibition of TNBC cells. In the absence of CCN5, p27(Kip1) resides mostly in the cytoplasm, which is associated with the aggressive nature of cancer cells. Mechanistically, CCN5 inhibits Skp2 expression, which seems to stabilize the p27(Kip1) protein in these cells. On the other hand, CCN5 also recruits FOXO3a to mediate the transcriptional regulation of p27(Kip1). The recruitment of FOXO3a is achieved by the induction of its expression and activity through shifting from cytoplasm to the nucleus. Our data indicate that CCN5 blocks PI3K/AKT signaling to dephosphorylate at S318, S253 and Thr32 in FOXO3a for nuclear relocalization and activation of FOXO3a. Moreover, inhibition of α6β1 receptors diminishes CCN5 action on p27(Kip1) in TNBC cells. Collectively, these data suggest that CCN5 effectively inhibits TNBC growth through the accumulation and trafficking of p27(Kip1) via Skp2 and FOXO3a regulation, and thus, activation of CCN5 may have the therapeutic potential to kill TNBC.
authors.affiliation: 1] Cancer Research Unit, V.A. Medical Center, Kansas City, MO, USA [2] Division of Hematology and Oncology, Department of Medicine, University of Kansas Medical Center, Kansas City, MO, USA.
authors.forename: I
authors.initials: I
authors.lastname: Haque
authors.affiliation: 1] Cancer Research Unit, V.A. Medical Center, Kansas City, MO, USA [2] Division of Hematology and Oncology, Department of Medicine, University of Kansas Medical Center, Kansas City, MO, USA.
authors.forename: S
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Cancer Research Unit, V.A. Medical Center, Kansas City, MO, USA.
authors.forename: A
authors.initials: A
authors.lastname: De
authors.affiliation: 1] Cancer Research Unit, V.A. Medical Center, Kansas City, MO, USA [2] Division of Hematology and Oncology, Department of Medicine, University of Kansas Medical Center, Kansas City, MO, USA.
authors.forename: G
authors.initials: G
authors.lastname: Maity
authors.affiliation: 1] Cancer Research Unit, V.A. Medical Center, Kansas City, MO, USA [2] Department of Anatomy and Cell Biology and Department of Pathology, University of Kansas Medical Center, Kansas City, MO, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Cancer Research Unit, V.A. Medical Center, Kansas City, MO, USA.
authors.forename: M
authors.initials: M
authors.lastname: Majumdar
authors.affiliation: Cancer Research Unit, V.A. Medical Center, Kansas City, MO, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Jha
authors.affiliation: Cancer Research Unit, V.A. Medical Center, Kansas City, MO, USA.
authors.forename: D
authors.initials: D
authors.lastname: McGragor
authors.affiliation: 1] Cancer Research Unit, V.A. Medical Center, Kansas City, MO, USA [2] Division of Hematology and Oncology, Department of Medicine, University of Kansas Medical Center, Kansas City, MO, USA [3] Department of Anatomy and Cell Biology and Department of Pathology, University of Kansas Medical Center, Kansas City, MO, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D055511:CCN Intercellular Signaling Proteins / Q000502:physiology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D055550:Protein Stability; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000502:physiology*; D044786:S-Phase Kinase-Associated Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D055511:CCN Intercellular Signaling Proteins; C413323:CCN5 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27