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Galectin-3 silencing inhibits epirubicin-induced ATP binding cassette transporters and activates the mitochondrial apoptosis pathway via β-catenin/GSK-3β modulation in colorectal carcinoma.
PLoS One. 2013; 8(11):e82478.Plos

Abstract

Multidrug resistance (MDR), an unfavorable factor compromising the treatment efficacy of anticancer drugs, involves the upregulation of ATP binding cassette (ABC) transporters and induction of galectin-3 signaling. Galectin-3 plays an anti-apoptotic role in many cancer cells and regulates various pathways to activate MDR. Thus, the inhibition of galectin-3 has the potential to enhance the efficacy of the anticancer drug epirubicin. In this study, we examined the effects and mechanisms of silencing galectin-3 via RNA interference (RNAi) on the β-catenin/GSK-3β pathway in human colon adenocarcinoma Caco-2 cells. Galectin-3 knockdown increased the intracellular accumulation of epirubicin in Caco-2 cells; suppressed the mRNA expression of galectin-3, β-catenin, cyclin D1, c-myc, P-glycoprotein (P-gp), MDR-associated protein (MRP) 1, and MRP2; and downregulated the protein expression of P-gp, cyclin D1, galectin-3, β-catenin, c-Myc, and Bcl-2. Moreover, galectin-3 RNAi treatment significantly increased the mRNA level of GSK-3β, Bax, caspase-3, and caspase-9; remarkably increased the Bax-to-Bcl-2 ratio; and upregulated the GSK-3β and Bax protein expressions. Apoptosis was induced by galectin-3 RNAi and/or epirubicin as demonstrated by chromatin condensation, a higher sub-G1 phase proportion, and increased caspase-3 and caspase-9 activity, indicating an intrinsic/mitochondrial apoptosis pathway. Epirubicin-mediated resistance was effectively inhibited via galectin-3 RNAi treatment. However, these phenomena could be rescued after galectin-3 overexpression. We show for the first time that the silencing of galectin-3 sensitizes MDR cells to epirubicin by inhibiting ABC transporters and activating the mitochondrial pathway of apoptosis through modulation of the β-catenin/GSK-3β pathway in human colon cancer cells.

Authors+Show Affiliations

Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan ; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24303084

Citation

Lee, Yung-Kuo, et al. "Galectin-3 Silencing Inhibits Epirubicin-induced ATP Binding Cassette Transporters and Activates the Mitochondrial Apoptosis Pathway Via β-catenin/GSK-3β Modulation in Colorectal Carcinoma." PloS One, vol. 8, no. 11, 2013, pp. e82478.
Lee YK, Lin TH, Chang CF, et al. Galectin-3 silencing inhibits epirubicin-induced ATP binding cassette transporters and activates the mitochondrial apoptosis pathway via β-catenin/GSK-3β modulation in colorectal carcinoma. PLoS One. 2013;8(11):e82478.
Lee, Y. K., Lin, T. H., Chang, C. F., & Lo, Y. L. (2013). Galectin-3 silencing inhibits epirubicin-induced ATP binding cassette transporters and activates the mitochondrial apoptosis pathway via β-catenin/GSK-3β modulation in colorectal carcinoma. PloS One, 8(11), e82478. https://doi.org/10.1371/journal.pone.0082478
Lee YK, et al. Galectin-3 Silencing Inhibits Epirubicin-induced ATP Binding Cassette Transporters and Activates the Mitochondrial Apoptosis Pathway Via β-catenin/GSK-3β Modulation in Colorectal Carcinoma. PLoS One. 2013;8(11):e82478. PubMed PMID: 24303084.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Galectin-3 silencing inhibits epirubicin-induced ATP binding cassette transporters and activates the mitochondrial apoptosis pathway via β-catenin/GSK-3β modulation in colorectal carcinoma. AU - Lee,Yung-Kuo, AU - Lin,Tsung-Hsien, AU - Chang,Chuan-Fa, AU - Lo,Yu-Li, Y1 - 2013/11/26/ PY - 2013/07/29/received PY - 2013/11/01/accepted PY - 2013/12/5/entrez PY - 2013/12/5/pubmed PY - 2014/10/2/medline SP - e82478 EP - e82478 JF - PloS one JO - PLoS One VL - 8 IS - 11 N2 - Multidrug resistance (MDR), an unfavorable factor compromising the treatment efficacy of anticancer drugs, involves the upregulation of ATP binding cassette (ABC) transporters and induction of galectin-3 signaling. Galectin-3 plays an anti-apoptotic role in many cancer cells and regulates various pathways to activate MDR. Thus, the inhibition of galectin-3 has the potential to enhance the efficacy of the anticancer drug epirubicin. In this study, we examined the effects and mechanisms of silencing galectin-3 via RNA interference (RNAi) on the β-catenin/GSK-3β pathway in human colon adenocarcinoma Caco-2 cells. Galectin-3 knockdown increased the intracellular accumulation of epirubicin in Caco-2 cells; suppressed the mRNA expression of galectin-3, β-catenin, cyclin D1, c-myc, P-glycoprotein (P-gp), MDR-associated protein (MRP) 1, and MRP2; and downregulated the protein expression of P-gp, cyclin D1, galectin-3, β-catenin, c-Myc, and Bcl-2. Moreover, galectin-3 RNAi treatment significantly increased the mRNA level of GSK-3β, Bax, caspase-3, and caspase-9; remarkably increased the Bax-to-Bcl-2 ratio; and upregulated the GSK-3β and Bax protein expressions. Apoptosis was induced by galectin-3 RNAi and/or epirubicin as demonstrated by chromatin condensation, a higher sub-G1 phase proportion, and increased caspase-3 and caspase-9 activity, indicating an intrinsic/mitochondrial apoptosis pathway. Epirubicin-mediated resistance was effectively inhibited via galectin-3 RNAi treatment. However, these phenomena could be rescued after galectin-3 overexpression. We show for the first time that the silencing of galectin-3 sensitizes MDR cells to epirubicin by inhibiting ABC transporters and activating the mitochondrial pathway of apoptosis through modulation of the β-catenin/GSK-3β pathway in human colon cancer cells. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24303084/Galectin_3_silencing_inhibits_epirubicin_induced_ATP_binding_cassette_transporters_and_activates_the_mitochondrial_apoptosis_pathway_via_β_catenin/GSK_3β_modulation_in_colorectal_carcinoma_ L2 - https://dx.plos.org/10.1371/journal.pone.0082478 DB - PRIME DP - Unbound Medicine ER -