A plant alkaloid, veratridine, potentiates cancer chemosensitivity by UBXN2A-dependent inhibition of an oncoprotein, mortalin-2

Ammara Abdullah, Sanam Sane, Kate A. Branick, Jessica L. Freeling, Hongmin Wang, Dong Zhang, Khosrow Rezvani

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)23561-23581
Number of pages21
JournalOncotarget
Volume6
Issue number27
DOIs
StatePublished - Jan 1 2015

Fingerprint

Veratridine
Oncogene Proteins
Alkaloids
Neoplasms
Colonic Neoplasms
Fluorouracil
Liliaceae
Drug Therapy
mortalin
Etoposide
Adjuvant Chemotherapy
Transcriptional Activation
Cytoplasm
Proteins
Cell Death
Up-Regulation
Stem Cells
Therapeutics

Keywords

  • Chemotherapy
  • Mortalin-2
  • P53
  • UBXN2A
  • Veratridine

ASJC Scopus subject areas

  • Oncology

Cite this

A plant alkaloid, veratridine, potentiates cancer chemosensitivity by UBXN2A-dependent inhibition of an oncoprotein, mortalin-2. / Abdullah, Ammara; Sane, Sanam; Branick, Kate A.; Freeling, Jessica L.; Wang, Hongmin; Zhang, Dong; Rezvani, Khosrow.

In: Oncotarget, Vol. 6, No. 27, 01.01.2015, p. 23561-23581.

Research output: Contribution to journalArticle

Abdullah, Ammara ; Sane, Sanam ; Branick, Kate A. ; Freeling, Jessica L. ; Wang, Hongmin ; Zhang, Dong ; Rezvani, Khosrow. / A plant alkaloid, veratridine, potentiates cancer chemosensitivity by UBXN2A-dependent inhibition of an oncoprotein, mortalin-2. In: Oncotarget. 2015 ; Vol. 6, No. 27. pp. 23561-23581.
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