Date of Award
Spring 2026
Document Type
Honors Thesis
Department/Major
Basic Biomedical Science
First Advisor
Khosrow Rezvani
Second Advisor
Mark Bouska
Third Advisor
Morgan Eikanger
Keywords
Colorectal cancer, UBXN2A, Veratridine, 5-fluorouracil, Mortalin-2, Rictor/mTORC2 signaling, p53, Patient-derived xenograft cell lines
Subject Categories
Cancer Biology | Cell Biology | Oncology | Therapeutics
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related mortality, particularly in patients with metastatic CRC and/or those who have developed resistance to conventional chemotherapy. There has been a significant rise in early-onset CRC (EOCRC) incidences in patients under age 50. Due to lack of screening, these patients are commonly diagnosed in the later stages where there is a lack of effective therapies. This highlights the need for targeted therapies that address the molecular drivers of tumor progression and treatment resistance. UBXN2A is a tumor suppressor protein that regulates key oncogenic pathways in CRC, including Mortalin-2 (mot-2)-mediated p53 suppression and Rictor-dependent mTORC2 signaling. Pharmacologic upregulation of UBXN2A by Veratridine (VTD), a plant-derived alkaloid repurposed as an anti-cancer agent, is a novel therapeutic strategy capable of reducing metastatic CRC. VTD transcriptionally upregulates UBXN2A, resulting in Rictor ubiquitination and degradation by the 26S proteasome and consequently suppresses the tumorigenic mTORC2-AKT signaling pathway. This selective targeted therapy is different from the function of traditional cytotoxic agents such as 5-fluorouracil (5-FU). This study evaluated the effects of VTD on UBXN2A, mot-2, and Rictor expression in patient-derived xenograft (PDX) CRC models with diverse genetic and molecular backgrounds. Two early-onset CRC PDX cell lines (HROC113 and HROC173) and one late-onset CRC PDX cell line (HROC24) were treated with VTD and compared with 5-FU or DMSO (control). Rictor and Mot-2 protein expression and cellular compartmentalization were assessed using immunofluorescence, confocal microscopy, and image-based quantitative analysis. Across cells, VTD (100 µM) treatment reduced Rictor expression in all three cell lines, suggesting UBXN2A-mediated suppression of pro-metastatic mTORC2 signaling in both early- and late-onset CRC. Responses of mot-2 to VTD varied by cell line, reflecting tumor heterogeneity and possible epigenetic influences. In the late-onset model, an inverse relationship between UBXN2A and mot-2 further supported UBXN2A’s role in regulating oncogenic stress-survival pathways. Overall, these findings support VTD-mediated UBXN2A activation as a promising targeted strategy to limit metastatic progression and overcome treatment resistance in CRC.
Recommended Citation
Schraufnagel, Kate S., "Differential Effects of Veratridine and 5-Fluorouracil on UBXN2A-Targeted Mortalin and Rictor Proteins in Patient-Derived Colorectal Cancer Cells" (2026). Honors Thesis. 416.
https://red.library.usd.edu/honors-thesis/416