Skip to main content
Top
Published in: Tumor Biology 9/2016

01-09-2016 | Original Article

Galectin-3 induces ovarian cancer cell survival and chemoresistance via TLR4 signaling activation

Authors: Guoqing Cai, Xiangdong Ma, Biliang Chen, Yanhong Huang, Shujuan Liu, Hong Yang, Wei Zou

Published in: Tumor Biology | Issue 9/2016

Login to get access

Abstract

Paclitaxel resistance becomes common in patients with aggressive ovarian cancer and results in recurrence after conventional therapy. Galectin-3 is a multifunctional lectin associated with cell migration, cell proliferation, cell adhesion, and cell-cell interaction in tumor cells. Whether circulating galectin-3 is involved in paclitaxel resistance in ovarian cancer remains unknown. The current study investigated the effect of galectin-3 on toll-like receptor 4 (TLR4) signaling and thus paclitaxel resistance. With blood and cancer tissue samples obtained from 102 patients, we identified associations between serum galectin-3 level or TLR4 expression and paclitaxel resistance phenotype. In vitro, treatment with exogenous galectin-3 restored cell survival and migration of SKOV-3 and ES-2 cells was decreased by galectin-3 silencing and paclitaxel treatment. Furthermore, exogenous galectin-3 boosted expression of TLR4, MyD88, and p-p65, as well as interleukin (IL)-6, IL-8, and vascular endothelial growth factor (VEGF) release induced by paclitaxel. Moreover, galectin-3 inhibited the interaction between TLR4 and caveolin-1 (Cav-1) in SKOV-3 and ES-2 cells. In addition, overexpression of Cav-1 dampened the expression of MyD88 and p-p65 stimulated by galectin-3 and enhanced apoptosis in SKOV-3 cells under paclitaxel exposure. In summary, our study elucidated that exogenous galectin-3 might induce paclitaxel resistance through TLR4 signaling activation by inhibiting TLR4-Cav-1 interaction, revealing a novel insight into paclitaxel resistance induction.
Literature
1.
go back to reference Chen VW, Ruiz B, Killeen JL, Cote TR, Wu XC, Correa CN. Pathology and classification of ovarian tumors. Cancer. 2003;97:2631–42.CrossRefPubMed Chen VW, Ruiz B, Killeen JL, Cote TR, Wu XC, Correa CN. Pathology and classification of ovarian tumors. Cancer. 2003;97:2631–42.CrossRefPubMed
2.
go back to reference Soslow RA. Histologic subtypes of ovarian carcinoma: an overview. Int J Gynecol Pathol. 2008;27:161–74.PubMed Soslow RA. Histologic subtypes of ovarian carcinoma: an overview. Int J Gynecol Pathol. 2008;27:161–74.PubMed
3.
4.
go back to reference Stewart LM, Holman CD, Finn JC, Preen DB, Hart R. In vitro fertilization is associated with an increased risk of borderline ovarian tumours. Gynecol Oncol. 2013;129:372–6.CrossRefPubMed Stewart LM, Holman CD, Finn JC, Preen DB, Hart R. In vitro fertilization is associated with an increased risk of borderline ovarian tumours. Gynecol Oncol. 2013;129:372–6.CrossRefPubMed
5.
go back to reference Smoter M, Bodnar L, Grala B, Stec R, Zieniuk K, Kozlowski W, et al. Tau protein as a potential predictive marker in epithelial ovarian cancer patients treated with paclitaxel/platinum first-line chemotherapy. J Exp Clin Cancer Res. 2013;32:25.CrossRefPubMedPubMedCentral Smoter M, Bodnar L, Grala B, Stec R, Zieniuk K, Kozlowski W, et al. Tau protein as a potential predictive marker in epithelial ovarian cancer patients treated with paclitaxel/platinum first-line chemotherapy. J Exp Clin Cancer Res. 2013;32:25.CrossRefPubMedPubMedCentral
6.
go back to reference Matsuo K, Eno ML, Im DD, Rosenshein NB, Sood AK. Clinical relevance of extent of extreme drug resistance in epithelial ovarian carcinoma. Gynecol Oncol. 2010;116:61–5.CrossRefPubMed Matsuo K, Eno ML, Im DD, Rosenshein NB, Sood AK. Clinical relevance of extent of extreme drug resistance in epithelial ovarian carcinoma. Gynecol Oncol. 2010;116:61–5.CrossRefPubMed
7.
go back to reference Salani R, Kurman RJ, Giuntoli 2nd R, Gardner G, Bristow R, Wang TL, et al. Assessment of tp53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance. Int J Gynecol Cancer. 2008;18:487–91.CrossRefPubMed Salani R, Kurman RJ, Giuntoli 2nd R, Gardner G, Bristow R, Wang TL, et al. Assessment of tp53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance. Int J Gynecol Cancer. 2008;18:487–91.CrossRefPubMed
8.
go back to reference Liu X, Gao Y, Lu Y, Zhang J, Li L, Yin F. Oncogenes associated with drug resistance in ovarian cancer. J Cancer Res Clin Oncol. 2015;141:381–95.CrossRefPubMed Liu X, Gao Y, Lu Y, Zhang J, Li L, Yin F. Oncogenes associated with drug resistance in ovarian cancer. J Cancer Res Clin Oncol. 2015;141:381–95.CrossRefPubMed
9.
go back to reference Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S, et al. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 2006;66:3859–68.CrossRefPubMed Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S, et al. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 2006;66:3859–68.CrossRefPubMed
10.
go back to reference d’Adhemar CJ, Spillane CD, Gallagher MF, Bates M, Costello KM, Barry-O’Crowley J, et al. The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer. PLoS One. 2014;9, e100816.CrossRefPubMedPubMedCentral d’Adhemar CJ, Spillane CD, Gallagher MF, Bates M, Costello KM, Barry-O’Crowley J, et al. The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer. PLoS One. 2014;9, e100816.CrossRefPubMedPubMedCentral
11.
go back to reference Szajnik M, Szczepanski MJ, Czystowska M, Elishaev E, Mandapathil M, Nowak-Markwitz E, et al. TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene. 2009;28:4353–63.CrossRefPubMedPubMedCentral Szajnik M, Szczepanski MJ, Czystowska M, Elishaev E, Mandapathil M, Nowak-Markwitz E, et al. TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene. 2009;28:4353–63.CrossRefPubMedPubMedCentral
12.
go back to reference Song L, Tang JW, Owusu L, Sun MZ, Wu J, Zhang J. Galectin-3 in cancer. Clin Chim Acta. 2014;431:185–91.CrossRefPubMed Song L, Tang JW, Owusu L, Sun MZ, Wu J, Zhang J. Galectin-3 in cancer. Clin Chim Acta. 2014;431:185–91.CrossRefPubMed
13.
14.
go back to reference Yilmaz H, Celik HT, Ozdemir O, Kalkan D, Namuslu M, Abusoglu S, et al. Serum galectin-3 levels in women with PCOS. J Endocrinol Invest. 2014;37:181–7.CrossRefPubMed Yilmaz H, Celik HT, Ozdemir O, Kalkan D, Namuslu M, Abusoglu S, et al. Serum galectin-3 levels in women with PCOS. J Endocrinol Invest. 2014;37:181–7.CrossRefPubMed
15.
go back to reference Barrow H, Guo X, Wandall HH, Pedersen JW, Fu B, Zhao Q, et al. Serum galectin-2, -4, and -8 are greatly increased in colon and breast cancer patients and promote cancer cell adhesion to blood vascular endothelium. Clin Cancer Res. 2011;17:7035–46.CrossRefPubMed Barrow H, Guo X, Wandall HH, Pedersen JW, Fu B, Zhao Q, et al. Serum galectin-2, -4, and -8 are greatly increased in colon and breast cancer patients and promote cancer cell adhesion to blood vascular endothelium. Clin Cancer Res. 2011;17:7035–46.CrossRefPubMed
16.
go back to reference Balan V, Wang Y, Nangia-Makker P, Kho D, Bajaj M, Smith D, et al. Galectin-3: a possible complementary marker to the PSA blood test. Oncotarget. 2013;4:542–9.CrossRefPubMedPubMedCentral Balan V, Wang Y, Nangia-Makker P, Kho D, Bajaj M, Smith D, et al. Galectin-3: a possible complementary marker to the PSA blood test. Oncotarget. 2013;4:542–9.CrossRefPubMedPubMedCentral
17.
go back to reference Eliaz I. The role of galectin-3 as a marker of cancer and inflammation in a stage IV ovarian cancer patient with underlying pro-inflammatory comorbidities. Case Rep Oncol. 2013;6:343–9.CrossRefPubMedPubMedCentral Eliaz I. The role of galectin-3 as a marker of cancer and inflammation in a stage IV ovarian cancer patient with underlying pro-inflammatory comorbidities. Case Rep Oncol. 2013;6:343–9.CrossRefPubMedPubMedCentral
18.
go back to reference Burguillos MA, Svensson M, Schulte T, Boza-Serrano A, Garcia-Quintanilla A, Kavanagh E, et al. Microglia-secreted galectin-3 acts as a toll-like receptor 4 ligand and contributes to microglial activation. Cell Rep 2015. Burguillos MA, Svensson M, Schulte T, Boza-Serrano A, Garcia-Quintanilla A, Kavanagh E, et al. Microglia-secreted galectin-3 acts as a toll-like receptor 4 ligand and contributes to microglial activation. Cell Rep 2015.
19.
go back to reference Arad U, Madar-Balakirski N, Angel-Korman A, Amir S, Tzadok S, Segal O, et al. Galectin-3 is a sensor-regulator of toll-like receptor pathways in synovial fibroblasts. Cytokine. 2015;73:30–5.CrossRefPubMed Arad U, Madar-Balakirski N, Angel-Korman A, Amir S, Tzadok S, Segal O, et al. Galectin-3 is a sensor-regulator of toll-like receptor pathways in synovial fibroblasts. Cytokine. 2015;73:30–5.CrossRefPubMed
20.
go back to reference Wang AC, Ma YB, Wu FX, Ma ZF, Liu NF, Gao R, et al. TLR4 induces tumor growth and inhibits paclitaxel activity in MyD88-positive human ovarian carcinoma. Oncol Lett. 2014;7:871–7.PubMed Wang AC, Ma YB, Wu FX, Ma ZF, Liu NF, Gao R, et al. TLR4 induces tumor growth and inhibits paclitaxel activity in MyD88-positive human ovarian carcinoma. Oncol Lett. 2014;7:871–7.PubMed
21.
go back to reference Wiechen K, Diatchenko L, Agoulnik A, Scharff KM, Schober H, Arlt K, et al. Caveolin-1 is down-regulated in human ovarian carcinoma and acts as a candidate tumor suppressor gene. Am J Pathol. 2001;159:1635–43.CrossRefPubMedPubMedCentral Wiechen K, Diatchenko L, Agoulnik A, Scharff KM, Schober H, Arlt K, et al. Caveolin-1 is down-regulated in human ovarian carcinoma and acts as a candidate tumor suppressor gene. Am J Pathol. 2001;159:1635–43.CrossRefPubMedPubMedCentral
22.
go back to reference Wang XM, Kim HP, Nakahira K, Ryter SW, Choi AM. The heme oxygenase-1/carbon monoxide pathway suppresses TLR4 signaling by regulating the interaction of TLR4 with caveolin-1. J Immunol. 2009;182:3809–18.CrossRefPubMed Wang XM, Kim HP, Nakahira K, Ryter SW, Choi AM. The heme oxygenase-1/carbon monoxide pathway suppresses TLR4 signaling by regulating the interaction of TLR4 with caveolin-1. J Immunol. 2009;182:3809–18.CrossRefPubMed
23.
go back to reference Harazono Y, Kho DH, Balan V, Nakajima K, Hogan V, Raz A. Extracellular galectin-3 programs multidrug resistance through Na+/K+-ATPase and p-glycoprotein signaling. Oncotarget. 2015;6:19592–604.CrossRefPubMedPubMedCentral Harazono Y, Kho DH, Balan V, Nakajima K, Hogan V, Raz A. Extracellular galectin-3 programs multidrug resistance through Na+/K+-ATPase and p-glycoprotein signaling. Oncotarget. 2015;6:19592–604.CrossRefPubMedPubMedCentral
24.
go back to reference Zhang H, Luo M, Liang X, Wang D, Gu X, Duan C, et al. Galectin-3 as a marker and potential therapeutic target in breast cancer. PLoS One. 2014;9, e103482.CrossRefPubMedPubMedCentral Zhang H, Luo M, Liang X, Wang D, Gu X, Duan C, et al. Galectin-3 as a marker and potential therapeutic target in breast cancer. PLoS One. 2014;9, e103482.CrossRefPubMedPubMedCentral
25.
go back to reference Mirandola L, Yu Y, Cannon MJ, Jenkins MR, Rahman RL, Nguyen DD, et al. Galectin-3 inhibition suppresses drug resistance, motility, invasion and angiogenic potential in ovarian cancer. Gynecol Oncol. 2014;135:573–9.CrossRefPubMed Mirandola L, Yu Y, Cannon MJ, Jenkins MR, Rahman RL, Nguyen DD, et al. Galectin-3 inhibition suppresses drug resistance, motility, invasion and angiogenic potential in ovarian cancer. Gynecol Oncol. 2014;135:573–9.CrossRefPubMed
26.
go back to reference Hossein G, Keshavarz M, Ahmadi S, Naderi N. Synergistic effects of pectasol-c modified citrus pectin an inhibitor of galectin-3 and paclitaxel on apoptosis of human SKOV-3 ovarian cancer cells. Asian Pac J Cancer Prev. 2013;14:7561–8.CrossRefPubMed Hossein G, Keshavarz M, Ahmadi S, Naderi N. Synergistic effects of pectasol-c modified citrus pectin an inhibitor of galectin-3 and paclitaxel on apoptosis of human SKOV-3 ovarian cancer cells. Asian Pac J Cancer Prev. 2013;14:7561–8.CrossRefPubMed
27.
28.
go back to reference Volk-Draper L, Hall K, Griggs C, Rajput S, Kohio P, DeNardo D, et al. Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner. Cancer Res. 2014;74:5421–34.CrossRefPubMedPubMedCentral Volk-Draper L, Hall K, Griggs C, Rajput S, Kohio P, DeNardo D, et al. Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner. Cancer Res. 2014;74:5421–34.CrossRefPubMedPubMedCentral
29.
go back to reference Schlegel A, Pestell RG, Lisanti MP. Caveolins in cholesterol trafficking and signal transduction: implications for human disease. Front Biosci. 2000;5:D929–937.CrossRefPubMed Schlegel A, Pestell RG, Lisanti MP. Caveolins in cholesterol trafficking and signal transduction: implications for human disease. Front Biosci. 2000;5:D929–937.CrossRefPubMed
30.
go back to reference Galbiati F, Razani B, Lisanti MP. Emerging themes in lipid rafts and caveolae. Cell. 2001;106:403–11.CrossRefPubMed Galbiati F, Razani B, Lisanti MP. Emerging themes in lipid rafts and caveolae. Cell. 2001;106:403–11.CrossRefPubMed
31.
go back to reference Quann K, Gonzales DM, Mercier I, Wang C, Sotgia F, Pestell RG, et al. Caveolin-1 is a negative regulator of tumor growth in glioblastoma and modulates chemosensitivity to temozolomide. Cell Cycle. 2013;12:1510–20.CrossRefPubMedPubMedCentral Quann K, Gonzales DM, Mercier I, Wang C, Sotgia F, Pestell RG, et al. Caveolin-1 is a negative regulator of tumor growth in glioblastoma and modulates chemosensitivity to temozolomide. Cell Cycle. 2013;12:1510–20.CrossRefPubMedPubMedCentral
32.
go back to reference Wang XM, Kim HP, Song R, Choi AM. Caveolin-1 confers antiinflammatory effects in murine macrophages via the MKK3/p38 MAPK pathway. Am J Respir Cell Mol Biol. 2006;34:434–42.CrossRefPubMed Wang XM, Kim HP, Song R, Choi AM. Caveolin-1 confers antiinflammatory effects in murine macrophages via the MKK3/p38 MAPK pathway. Am J Respir Cell Mol Biol. 2006;34:434–42.CrossRefPubMed
33.
go back to reference Garrean S, Gao XP, Brovkovych V, Shimizu J, Zhao YY, Vogel SM, et al. Caveolin-1 regulates NF-kappaB activation and lung inflammatory response to sepsis induced by lipopolysaccharide. J Immunol. 2006;177:4853–60.CrossRefPubMed Garrean S, Gao XP, Brovkovych V, Shimizu J, Zhao YY, Vogel SM, et al. Caveolin-1 regulates NF-kappaB activation and lung inflammatory response to sepsis induced by lipopolysaccharide. J Immunol. 2006;177:4853–60.CrossRefPubMed
34.
go back to reference Jiao H, Zhang Y, Yan Z, Wang ZG, Liu G, Minshall RD, et al. Caveolin-1 Tyr14 phosphorylation induces interaction with TLR4 in endothelial cells and mediates MyD88-dependent signaling and sepsis-induced lung inflammation. J Immunol. 2013;191:6191–9.CrossRefPubMed Jiao H, Zhang Y, Yan Z, Wang ZG, Liu G, Minshall RD, et al. Caveolin-1 Tyr14 phosphorylation induces interaction with TLR4 in endothelial cells and mediates MyD88-dependent signaling and sepsis-induced lung inflammation. J Immunol. 2013;191:6191–9.CrossRefPubMed
Metadata
Title
Galectin-3 induces ovarian cancer cell survival and chemoresistance via TLR4 signaling activation
Authors
Guoqing Cai
Xiangdong Ma
Biliang Chen
Yanhong Huang
Shujuan Liu
Hong Yang
Wei Zou
Publication date
01-09-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 9/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-016-5038-6

Other articles of this Issue 9/2016

Tumor Biology 9/2016 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine