Evaluation of potential targets to enhance the sensitivity of cholangiocarcinoma cells to anticancer drugs

Paula Sanchon-Sanchez; Oscar Briz; Rocio I.R. Macias; Mar Abad; Anabel Sanchez-Martin; Jose J.G. Marin; Elisa Lozano

Biomedicine & Pharmacotherapy (Dec 2023)

Evaluation of potential targets to enhance the sensitivity of cholangiocarcinoma cells to anticancer drugs

Paula Sanchon-Sanchez,
Oscar Briz,
Rocio I.R. Macias,
Mar Abad,
Anabel Sanchez-Martin,
Jose J.G. Marin,
Elisa Lozano

Affiliations

Paula Sanchon-Sanchez: Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain
Oscar Briz: Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain
Rocio I.R. Macias: Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain
Mar Abad: Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Department of Pathology, University of Salamanca, Salamanca, Spain
Anabel Sanchez-Martin: Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
Jose J.G. Marin: Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain; Correspondence to: Department of Physiology and Pharmacology, University of Salamanca, Campus Miguel de Unamuno, E.D. Lab-231, 37007 Salamanca, Spain.
Elisa Lozano: Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain

Journal volume & issue: Vol. 168
p. 115658

Abstract

Read online

Background: Cholangiocarcinoma (CCA) is a highly lethal cancer originated in the biliary tree. Available treatments for CCA are scarcely effective, partly due to mechanisms of chemoresistance, such as aberrant activation of Wnt/β-catenin pathway and dysfunctional p53. Aim: To evaluate the impact of enhancing the expression of negative regulators of the Wnt/β-catenin pathway (AXIN1, AXIN2, and GSK3B) and the tumor suppressor gene TP53. Methods: Gene expression in paired samples of CCA and adjacent non-tumor liver tissue was determined by RT-qPCR and immunohistochemistry (IHC). Using lentiviral vectors, CCA cells were transduced with genes of interest to assess their impact on the resistome (TLDA), apoptosis (annexin V/propidium iodide), and decreased cell viability (MTT). Results: IHC revealed marked nuclear localization of β-catenin, consistent with Wnt/β-catenin pathway activation. In silico analysis with data from TCGA showed heterogeneous down-regulation of AXIN1, AXIN2, and GSK3B in CCA. Enhancing the expression of AXIN1, AXIN2, and GSK3B in CCA cells was not enough to block the activity of this signaling pathway or significantly modify resistance to 5-FU, gemcitabine, and platinated drugs. Consistent with impaired p53 function, CDKN1A was down-regulated in CCA. Forced TP53 expression induced p21 up-regulation and reduced cell proliferation. Moreover, the resistome was modified (FAS, BAX, TYMP, and CES2 up-regulation along with DHFR, RRM1, and BIRC5 down-regulation), which was accompanied by enhanced sensitivity to some antitumor drugs, mainly platinated drugs. Conclusion: Enhancing TP53 expression, but not that of AXIN1, AXIN2, and GSK3B, in CCA cells may be a useful strategy to sensitize CCA to antitumor drugs.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

About the journal

Abstract

Keywords