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

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

doi:10.18632/oncotarget.4452

Ammara Abdullah, Kate A Branick + Show 5 more

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https://doi.org/10.18632/oncotarget.4452

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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.

Highlights

The heat shock protein mortalin-2 excludes wild-type (WT)-p53 from the nucleus and eventually targets p53 protein for proteasomal degradation [1]
To verify whether VTD-induced cell death is mediated through the UBXN2A-mot-2-p53 axis [4], we looked at the expression of p53 in the cytoplasm and nucleus of HCT-116 cells following VTD treatment
We showed that UBXN2A enhancement leads to apoptosis at the cellular level and in live animals, resulting in tumor growth suppression

Summary

Introduction

The heat shock protein mortalin-2 (mot-2) excludes wild-type (WT)-p53 from the nucleus and eventually targets p53 protein for proteasomal degradation [1]. We have previously shown that a Ubiquitinlike (UBX)-domain-containing protein, UBXN2A, binds to and inactivates the mot-2 oncoprotein. UBXN2A expression is sufficient to re-activate WT-p53 through a mechanism of competitive interaction with mot-2 [4]. This novel protein complex (UBXN2A-mot-2) exists only in the cytoplasm of cancer cells and not in normal cells due to the dominant mitochondrial localization of mot-2 in normal cells [5]. Therapy that targets the UBXN2A-mot-2 complex will not affect normal cells. MKT-077 and withanone were reported as mot-2 small molecule inhibitors [6, 7]. Several unacceptable side effects were observed when MKT-077 was used in a clinical trial [8]

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