title: A plant alkaloid, veratridine, potentiates cancer chemosensitivity by UBXN2A-dependent inhibition of an oncoprotein, mortalin-2.
abstract: Veratridine (VTD), an alkaloid derived from the Liliaceae plant shows anti-tumor effects; however, its molecular targets have not been thoroughly studied. Using a high-throughput drug screen, we found that VTD enhances transactivation of UBXN2A, resulting in upregulation of UBXN2A in the cytoplasm, where UBXN2A binds and inhibits the oncoprotein mortalin-2 (mot-2). VTD-treated cancer cells undergo cell death in UBXN2A- and mot-2-dependent manners. The cytotoxic function of VTD is grade-dependent, and the combined treatment with a sub-optimal dose of the standard chemotherapy, 5-Fluorouracil (5-FU) and etoposide, demonstrated a synergistic effect, resulting in higher therapeutic efficacy. VTD influences the CD44+ stem cells, possibly through UBXN2A-dependent inhibition of mot-2. The VTD-dependent expression of UBXN2A is a potential candidate for designing novel strategies for colon cancer treatment because: 1) In 50% of colon cancer patients, UBXN2A protein levels in tumor tissues are significantly lower than those in the adjacent normal tissues. 2) Cytoplasmic expression of the mot-2 protein is very low in non-cancerous cells; thus, VTD can produce tumor-specific toxicity while normal cells remain intact. 3) Finally, VTD or its modified analogs offer a valuable adjuvant chemotherapy strategy to improve the efficacy of 5-FU-based chemotherapy for colon cancer patients harboring WT-p53.
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Ammara
authors.initials: A
authors.lastname: Abdullah
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Sanam
authors.initials: S
authors.lastname: Sane
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Kate A
authors.initials: KA
authors.lastname: Branick
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Freeling
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY 11568, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Khosrow
authors.initials: K
authors.lastname: Rezvani
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D004742:Enhancer Elements, Genetic; D005047:Etoposide / Q000737:chemistry; D005260:Female; D005472:Fluorouracil / Q000737:chemistry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D045325:HCT116 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010936:Plant Extracts / Q000737:chemistry; D040081:Protein Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*; D014701:Veratridine / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018840:HSP70 Heat-Shock Proteins; C492001:HSPA9 protein, human; D018960:Hyaluronan Receptors; D024101:Mitochondrial Proteins; D010936:Plant Extracts; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000609706:UBXN2A protein, human; D025801:Ubiquitin; D014452:Ubiquitins; D049452:Green Fluorescent Proteins; D005047:Etoposide; D014701:Veratridine; D005472:Fluorouracil
keywords: UBXN2A; chemotherapy; mortalin-2; p53; veratridine