title: Wnt9A Induction Linked to Suppression of Human Colorectal Cancer Cell Proliferation.
abstract: Most studies of Wnt signaling in malignant tissues have focused on the canonical Wnt pathway (CWP) due to its role in stimulating cellular proliferation. The role of the non-canonical Wnt pathway (NCWP) in tissues with dysregulated Wnt signaling is not fully understood. Understanding NCWP's role is important since these opposing pathways act in concert to maintain homeostasis in healthy tissues. Our preliminary studies demonstrated that LiCl inhibited proliferation of primary cells derived from colorectal cancer (CRC). Since LiCl stimulates cell proliferation in normal tissues and NCWP suppresses it, the present study was designed to investigate the impact of NCWP components in LiCl-mediated effects. LiCl-mediated inhibition of CRC cell proliferation (p < 0.001) and increased apoptosis (p < 0.01) coincided with 23-fold increase (p < 0.025) in the expression of the NCWP ligand, Wnt9A. LiCl also suppressed β-catenin mRNA (p < 0.03), total β-catenin protein (p < 0.025) and the active form of β-catenin. LiCl-mediated inhibition of CRC cell proliferation was partially reversed by IWP-2, and Wnt9A antibody. Recombinant Wnt9A protein emulated LiCl effects by suppressing β-catenin protein (p < 0.001), inhibiting proliferation (p < 0.001) and increasing apoptosis (p < 0.03). This is the first study to demonstrate induction of a NCWP ligand, Wnt9A as part of a mechanism for LiCl-mediated suppression of CRC cell proliferation.
authors.affiliation: Senior Research Associate, Translational Research Laboratory, Cancer Treatment Centers of America<sup>®</sup>, 2520 Elisha Avenue, Zion, IL 60099, USA. Irshad.Ali@ctca-hope.com.
authors.forename: Irshad
authors.initials: I
authors.lastname: Ali
authors.affiliation: Research Associate, Translational Research Laboratory, Cancer Treatment Centers of America<sup>®</sup>, 2520 Elisha Avenue, Zion, IL 60099, USA. Bani.Fagla@ctca-hope.com.
authors.forename: Bani
authors.initials: B
authors.lastname: Medegan
authors.affiliation: VP Translational Research and Chief Science Officer, Cancer Treatment Centers of America<sup>®</sup>, 2610 Sheridan Rd., Zion, IL 60099, USA. Donald.Braun@ctca-hope.com.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Braun
mesh_terms: D000328:Adult; D018692:Antimanic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D008875:Middle Aged; D012007:Rectum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018692:Antimanic Agents; D000970:Antineoplastic Agents; C110670:WNT9A protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D018021:Lithium Chloride
keywords: LiCl; Wnt pathway ligand; Wnt9A; canonical Wnt pathway; human colorectal cancer; non-canonical Wnt pathway; β-catenin