Targeting galectin-1 impairs castration-resistant prostate cancer progression and invasion

T.-C. Shih, R. Liu, C.-T. Wu, X. Li, W. Xiao, X. Deng, S. Kiss, T. Wang, X.-J. Chen, R. Carney, H.-J. Kung, Y. Duan, P.M. Ghosh, K.S. Lam

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Purpose: The majority of patients with prostate cancer who are treated with androgen-deprivation therapy (ADT) will eventually develop fatal metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no effective durable therapies for patients with mCRPC. High expression of galectin-1 (Gal-1) is associated with prostate cancer progression and poor clinical outcome. The role of Gal-1 in tumor progression is largely unknown. Here, we characterized Gal-1 functions and evaluated the therapeutic effects of a newly developed Gal-1 inhibitor, LLS30, in mCRPC. Experimental Design: Cell viability, colony formation, migration, and invasion assays were performed to examine the effects of inhibition of Gal-1 in CRPC cells. We used two human CRPC xenograft models to assess growth-inhibitory effects of LLS30. Genome-wide gene expression analysis was conducted to elucidate the effects of LLS30 on metastatic PC3 cells. Results: Gal-1 was highly expressed in CRPC cells, but not in androgen-sensitive cells. Gal-1 knockdown significantly inhibited CRPC cells' growth, anchorage-independent growth, migration, and invasion through the suppression of androgen receptor (AR) and Akt signaling. LLS30 targets Gal-1 as an allosteric inhibitor and decreases Gal-1–binding affinity to its binding partners. LLS30 showed in vivo efficacy in both AR-positive and AR-negative xenograft models. LLS30 not only can potentiate the antitumor effect of docetaxel to cause complete regression of tumors, but can also effectively inhibit the invasion and metastasis of prostate cancer cells in vivo. Conclusions: Our study provides evidence that Gal-1 is an important target for mCRPC therapy, and LLS30 is a promising small-molecule compound that can potentially overcome mCRPC. © 2018 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)4319-4331
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number17
DOIs
Publication statusPublished - 2018

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Galectin 1
Castration
Prostatic Neoplasms
Androgen Receptors
docetaxel
Heterografts
Androgens
Growth
Therapeutic Uses
Neoplasms
Cell Survival
Research Design
Therapeutics
Genome
Neoplasm Metastasis
Gene Expression

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Targeting galectin-1 impairs castration-resistant prostate cancer progression and invasion. / Shih, T.-C.; Liu, R.; Wu, C.-T.; Li, X.; Xiao, W.; Deng, X.; Kiss, S.; Wang, T.; Chen, X.-J.; Carney, R.; Kung, H.-J.; Duan, Y.; Ghosh, P.M.; Lam, K.S.

In: Clinical Cancer Research, Vol. 24, No. 17, 2018, p. 4319-4331.

Research output: Contribution to journalArticle

Shih, T-C, Liu, R, Wu, C-T, Li, X, Xiao, W, Deng, X, Kiss, S, Wang, T, Chen, X-J, Carney, R, Kung, H-J, Duan, Y, Ghosh, PM & Lam, KS 2018, 'Targeting galectin-1 impairs castration-resistant prostate cancer progression and invasion', Clinical Cancer Research, vol. 24, no. 17, pp. 4319-4331. https://doi.org/10.1158/1078-0432.CCR-18-0157
Shih, T.-C. ; Liu, R. ; Wu, C.-T. ; Li, X. ; Xiao, W. ; Deng, X. ; Kiss, S. ; Wang, T. ; Chen, X.-J. ; Carney, R. ; Kung, H.-J. ; Duan, Y. ; Ghosh, P.M. ; Lam, K.S. / Targeting galectin-1 impairs castration-resistant prostate cancer progression and invasion. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 17. pp. 4319-4331.
@article{40ac2bcaca5a4853b4619bfc48865bb0,
title = "Targeting galectin-1 impairs castration-resistant prostate cancer progression and invasion",
abstract = "Purpose: The majority of patients with prostate cancer who are treated with androgen-deprivation therapy (ADT) will eventually develop fatal metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no effective durable therapies for patients with mCRPC. High expression of galectin-1 (Gal-1) is associated with prostate cancer progression and poor clinical outcome. The role of Gal-1 in tumor progression is largely unknown. Here, we characterized Gal-1 functions and evaluated the therapeutic effects of a newly developed Gal-1 inhibitor, LLS30, in mCRPC. Experimental Design: Cell viability, colony formation, migration, and invasion assays were performed to examine the effects of inhibition of Gal-1 in CRPC cells. We used two human CRPC xenograft models to assess growth-inhibitory effects of LLS30. Genome-wide gene expression analysis was conducted to elucidate the effects of LLS30 on metastatic PC3 cells. Results: Gal-1 was highly expressed in CRPC cells, but not in androgen-sensitive cells. Gal-1 knockdown significantly inhibited CRPC cells' growth, anchorage-independent growth, migration, and invasion through the suppression of androgen receptor (AR) and Akt signaling. LLS30 targets Gal-1 as an allosteric inhibitor and decreases Gal-1–binding affinity to its binding partners. LLS30 showed in vivo efficacy in both AR-positive and AR-negative xenograft models. LLS30 not only can potentiate the antitumor effect of docetaxel to cause complete regression of tumors, but can also effectively inhibit the invasion and metastasis of prostate cancer cells in vivo. Conclusions: Our study provides evidence that Gal-1 is an important target for mCRPC therapy, and LLS30 is a promising small-molecule compound that can potentially overcome mCRPC. {\circledC} 2018 American Association for Cancer Research.",
author = "T.-C. Shih and R. Liu and C.-T. Wu and X. Li and W. Xiao and X. Deng and S. Kiss and T. Wang and X.-J. Chen and R. Carney and H.-J. Kung and Y. Duan and P.M. Ghosh and K.S. Lam",
note = "Export Date: 30 October 2018 CODEN: CCREF 通訊地址: Lam, K.S.; UC Davis NCI-designated Comprehensive Cancer Center, University of California, DavisUnited States; 電子郵件: kslam@ucdavis.edu 參考文獻: Siegel, R.L., Miller, K.D., Jemal, A., Cancer statistics, 2017 (2017) CA Cancer J Clin, 67, pp. 7-30; Huggins, C., Hodges, C.V., The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate (1941) Cancer Res, 1, pp. 293-297; Cookson, M.S., Roth, B.J., Dahm, P., Engstrom, C., Freedland, S.J., Hussain, M., Castration-resistant prostate cancer: AUA guideline (2013) J Urol, 190, pp. 429-438; Zhang, P., Zhang, P., Shi, B., Zhou, M., Jiang, H., Zhang, H., Galectin-1 overexpression promotes progression and chemoresistance to cisplatin in epithelial ovarian cancer (2014) Cell Death Dis, 5, p. e991; Carlini, M.J., Roitman, P., Nunez, M., Pallotta, M.G., Boggio, G., Smith, D., Clinical relevance of galectin-1 expression in non-small cell lung cancer patients (2014) Lung Cancer, 84, pp. 73-78; Jung, E.J., Moon, H.G., Cho, B.I., Jeong, C.Y., Joo, Y.T., Lee, Y.J., Galectin-1 expression in cancer-associated stromal cells correlates tumor invasiveness and tumor progression in breast cancer (2007) Int J Cancer, 120, pp. 2331-2338; White, N.M., Masui, O., Newsted, D., Scorilas, A., Romaschin, A.D., Bjarnason, G.A., Galectin-1 has potential prognostic significance and is implicated in clear cell renal cell carcinoma progression through the HIF/mTOR signaling axis (2014) Br J Cancer, 110, pp. 1250-1259; Martinez-Bosch, N., Fernandez-Barrena, M.G., Moreno, M., Ortiz-Zapater, E., Munne-Collado, J., Iglesias, M., Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and hedgehog signaling activation (2014) Cancer Res, 74, pp. 3512-3524; Liu, F.T., Rabinovich, G.A., Galectins as modulators of tumour progression (2005) Nat Rev Cancer, 5, pp. 29-41; Perillo, N.L., Pace, K.E., Seilhamer, J.J., Baum, L.G., Apoptosis of T cells mediated by galectin-1 (1995) Nature, 378, pp. 736-739; Rubinstein, N., Alvarez, M., Zwirner, N.W., Toscano, M.A., Ilarregui, J.M., Bravo, A., Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection (2004) Cancer Cell, 5, pp. 241-251; Fischer, C., Sanchez-Ruderisch, H., Welzel, M., Wiedenmann, B., Sakai, T., Andre, S., Galectin-1 interacts with the a5b1 fibronectin receptor to restrict carcinoma cell growth via induction of p21 and p27 (2005) J Biol Chem, 280, pp. 37266-37277; Wells, V., Davies, D., Mallucci, L., Cell cycle arrest and induction of apoptosis by beta galactoside binding protein (beta GBP) in human mammary cancer cells. A potential new approach to cancer control (1999) Eur J Cancer, 35, pp. 978-983; Stanley, P., Galectin-1 pulls the strings on VEGFR2 (2014) Cell, 156, pp. 625-626; Hsu, Y.L., Wu, C.Y., Hung, J.Y., Lin, Y.S., Huang, M.S., Kuo, P.L., Galectin-1 promotes lung cancer tumor metastasis by potentiating integrin alpha6beta4 and Notch1/Jagged2 signaling pathway (2013) Carcinogenesis, 34, pp. 1370-1381; Qian, D., Lu, Z., Xu, Q., Wu, P., Tian, L., Zhao, L., Galectin-1-driven upregulation of SDF-1 in pancreatic stellate cells promotes pancreatic cancer metastasis (2017) Cancer Lett, 397, pp. 43-51; Wu, M.-H., Hong, T.-M., Cheng, H.-W., Pan, S.-H., Liang, Y.-R., Hong, H.-C., Galectin-1-mediated tumor invasion and metastasis, up-regulated matrix metalloproteinase expression, and reorganized actin cytoskeletons (2009) Mol Cancer Res, 7, pp. 311-318; van den Br{\^u}le, F.A., Waltregny, D., Castronovo, V., Increased expression of galectin-1 in carcinoma-associated stroma predicts poor outcome in prostate carcinoma patients (2001) J Pathol, 193, pp. 80-87; Laderach, D.J., Gentilini, L.D., Giribaldi, L., Delgado, V.C., Nugnes, L., Croci, D.O., A unique galectin signature in human prostate cancer progression suggests galectin-1 as a key target for treatment of advanced disease (2013) Cancer Res, 73, pp. 86-96; Shih, T.-C., Liu, R., Fung, G., Bhardwaj, G., Ghosh, P.M., Lam, K.S., Anovelgalectin-1 inhibitor discovered through one-bead-two-compounds library potentiates the anti-tumor effects of paclitaxel in vivo (2017) Mol Cancer Ther, 6, pp. 1212-1223; Blanchard, H., Bum-Erdene, K., Bohari, M.H., Yu, X., Galectin-1 inhibitors and their potential therapeutic applications: A patent review (2016) Expert Opin Ther Pat, 26, pp. 537-554; Epstein, J.I., Allsbrook, W.C., Jr, Amin, M.B., Egevad, L.L., The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma (2005) Am J Surg Pathol, 29, pp. 1228-1242; Hsieh, S.Y., Shih, T.C., Yeh, C.Y., Lin, C.J., Chou, Y.Y., Lee, Y.S., Comparative proteomic studies on the pathogenesis of human ulcerative colitis (2006) Prote-Omics, 6, pp. 5322-5331; Laderach, D.J., Gentilini, L.D., Giribaldi, L., Delgado, V.C., Nugnes, L., Croci, D.O., A unique galectin signature in human prostate cancer progression suggests galectin-1 as a key target for treatment of advanced disease (2013) Cancer Res, 73, pp. 86-96; Shih, T.-C., Liu, R., Fung, G., Bhardwaj, G., Ghosh, P.M., Lam, K.S., A novel galectin-1 inhibitor discovered through one-bead two-compound library potentiates the antitumor effects of paclitaxel in vivo (2017) Mol Cancer Ther, 16, pp. 1212-1223; Moiseeva, E.P., Williams, B., Samani, N.J., Galectin 1 inhibits incorporation of vitronectin and chondroitin sulfate B into the extracellular matrix of human vascular smooth muscle cells (2003) Biochim Biophys Acta, 1619, pp. 125-132; Kinkade, C.W., Castillo-Martin, M., Puzio-Kuter, A., Yan, J., Foster, T.H., Gao, H., Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model (2008) J Clin Invest, 118, pp. 3051-3064; Sarker, D., Reid, A.H.M., Yap, T.A., De Bono, J.S., Targeting the PI3K/AKT pathway for the treatment of prostate cancer (2009) Clin Cancer Res, 15, pp. 4799-4805; 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year = "2018",
doi = "10.1158/1078-0432.CCR-18-0157",
language = "English",
volume = "24",
pages = "4319--4331",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "17",

}

TY - JOUR

T1 - Targeting galectin-1 impairs castration-resistant prostate cancer progression and invasion

AU - Shih, T.-C.

AU - Liu, R.

AU - Wu, C.-T.

AU - Li, X.

AU - Xiao, W.

AU - Deng, X.

AU - Kiss, S.

AU - Wang, T.

AU - Chen, X.-J.

AU - Carney, R.

AU - Kung, H.-J.

AU - Duan, Y.

AU - Ghosh, P.M.

AU - Lam, K.S.

N1 - Export Date: 30 October 2018 CODEN: CCREF 通訊地址: Lam, K.S.; UC Davis NCI-designated Comprehensive Cancer Center, University of California, DavisUnited States; 電子郵件: kslam@ucdavis.edu 參考文獻: Siegel, R.L., Miller, K.D., Jemal, A., Cancer statistics, 2017 (2017) CA Cancer J Clin, 67, pp. 7-30; Huggins, C., Hodges, C.V., The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate (1941) Cancer Res, 1, pp. 293-297; Cookson, M.S., Roth, B.J., Dahm, P., Engstrom, C., Freedland, S.J., Hussain, M., Castration-resistant prostate cancer: AUA guideline (2013) J Urol, 190, pp. 429-438; Zhang, P., Zhang, P., Shi, B., Zhou, M., Jiang, H., Zhang, H., Galectin-1 overexpression promotes progression and chemoresistance to cisplatin in epithelial ovarian cancer (2014) Cell Death Dis, 5, p. e991; Carlini, M.J., Roitman, P., Nunez, M., Pallotta, M.G., Boggio, G., Smith, D., Clinical relevance of galectin-1 expression in non-small cell lung cancer patients (2014) Lung Cancer, 84, pp. 73-78; Jung, E.J., Moon, H.G., Cho, B.I., Jeong, C.Y., Joo, Y.T., Lee, Y.J., Galectin-1 expression in cancer-associated stromal cells correlates tumor invasiveness and tumor progression in breast cancer (2007) Int J Cancer, 120, pp. 2331-2338; White, N.M., Masui, O., Newsted, D., Scorilas, A., Romaschin, A.D., Bjarnason, G.A., Galectin-1 has potential prognostic significance and is implicated in clear cell renal cell carcinoma progression through the HIF/mTOR signaling axis (2014) Br J Cancer, 110, pp. 1250-1259; Martinez-Bosch, N., Fernandez-Barrena, M.G., Moreno, M., Ortiz-Zapater, E., Munne-Collado, J., Iglesias, M., Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and hedgehog signaling activation (2014) Cancer Res, 74, pp. 3512-3524; Liu, F.T., Rabinovich, G.A., Galectins as modulators of tumour progression (2005) Nat Rev Cancer, 5, pp. 29-41; Perillo, N.L., Pace, K.E., Seilhamer, J.J., Baum, L.G., Apoptosis of T cells mediated by galectin-1 (1995) Nature, 378, pp. 736-739; Rubinstein, N., Alvarez, M., Zwirner, N.W., Toscano, M.A., Ilarregui, J.M., Bravo, A., Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection (2004) Cancer Cell, 5, pp. 241-251; Fischer, C., Sanchez-Ruderisch, H., Welzel, M., Wiedenmann, B., Sakai, T., Andre, S., Galectin-1 interacts with the a5b1 fibronectin receptor to restrict carcinoma cell growth via induction of p21 and p27 (2005) J Biol Chem, 280, pp. 37266-37277; Wells, V., Davies, D., Mallucci, L., Cell cycle arrest and induction of apoptosis by beta galactoside binding protein (beta GBP) in human mammary cancer cells. A potential new approach to cancer control (1999) Eur J Cancer, 35, pp. 978-983; Stanley, P., Galectin-1 pulls the strings on VEGFR2 (2014) Cell, 156, pp. 625-626; Hsu, Y.L., Wu, C.Y., Hung, J.Y., Lin, Y.S., Huang, M.S., Kuo, P.L., Galectin-1 promotes lung cancer tumor metastasis by potentiating integrin alpha6beta4 and Notch1/Jagged2 signaling pathway (2013) Carcinogenesis, 34, pp. 1370-1381; Qian, D., Lu, Z., Xu, Q., Wu, P., Tian, L., Zhao, L., Galectin-1-driven upregulation of SDF-1 in pancreatic stellate cells promotes pancreatic cancer metastasis (2017) Cancer Lett, 397, pp. 43-51; Wu, M.-H., Hong, T.-M., Cheng, H.-W., Pan, S.-H., Liang, Y.-R., Hong, H.-C., Galectin-1-mediated tumor invasion and metastasis, up-regulated matrix metalloproteinase expression, and reorganized actin cytoskeletons (2009) Mol Cancer Res, 7, pp. 311-318; van den Brûle, F.A., Waltregny, D., Castronovo, V., Increased expression of galectin-1 in carcinoma-associated stroma predicts poor outcome in prostate carcinoma patients (2001) J Pathol, 193, pp. 80-87; 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PY - 2018

Y1 - 2018

N2 - Purpose: The majority of patients with prostate cancer who are treated with androgen-deprivation therapy (ADT) will eventually develop fatal metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no effective durable therapies for patients with mCRPC. High expression of galectin-1 (Gal-1) is associated with prostate cancer progression and poor clinical outcome. The role of Gal-1 in tumor progression is largely unknown. Here, we characterized Gal-1 functions and evaluated the therapeutic effects of a newly developed Gal-1 inhibitor, LLS30, in mCRPC. Experimental Design: Cell viability, colony formation, migration, and invasion assays were performed to examine the effects of inhibition of Gal-1 in CRPC cells. We used two human CRPC xenograft models to assess growth-inhibitory effects of LLS30. Genome-wide gene expression analysis was conducted to elucidate the effects of LLS30 on metastatic PC3 cells. Results: Gal-1 was highly expressed in CRPC cells, but not in androgen-sensitive cells. Gal-1 knockdown significantly inhibited CRPC cells' growth, anchorage-independent growth, migration, and invasion through the suppression of androgen receptor (AR) and Akt signaling. LLS30 targets Gal-1 as an allosteric inhibitor and decreases Gal-1–binding affinity to its binding partners. LLS30 showed in vivo efficacy in both AR-positive and AR-negative xenograft models. LLS30 not only can potentiate the antitumor effect of docetaxel to cause complete regression of tumors, but can also effectively inhibit the invasion and metastasis of prostate cancer cells in vivo. Conclusions: Our study provides evidence that Gal-1 is an important target for mCRPC therapy, and LLS30 is a promising small-molecule compound that can potentially overcome mCRPC. © 2018 American Association for Cancer Research.

AB - Purpose: The majority of patients with prostate cancer who are treated with androgen-deprivation therapy (ADT) will eventually develop fatal metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no effective durable therapies for patients with mCRPC. High expression of galectin-1 (Gal-1) is associated with prostate cancer progression and poor clinical outcome. The role of Gal-1 in tumor progression is largely unknown. Here, we characterized Gal-1 functions and evaluated the therapeutic effects of a newly developed Gal-1 inhibitor, LLS30, in mCRPC. Experimental Design: Cell viability, colony formation, migration, and invasion assays were performed to examine the effects of inhibition of Gal-1 in CRPC cells. We used two human CRPC xenograft models to assess growth-inhibitory effects of LLS30. Genome-wide gene expression analysis was conducted to elucidate the effects of LLS30 on metastatic PC3 cells. Results: Gal-1 was highly expressed in CRPC cells, but not in androgen-sensitive cells. Gal-1 knockdown significantly inhibited CRPC cells' growth, anchorage-independent growth, migration, and invasion through the suppression of androgen receptor (AR) and Akt signaling. LLS30 targets Gal-1 as an allosteric inhibitor and decreases Gal-1–binding affinity to its binding partners. LLS30 showed in vivo efficacy in both AR-positive and AR-negative xenograft models. LLS30 not only can potentiate the antitumor effect of docetaxel to cause complete regression of tumors, but can also effectively inhibit the invasion and metastasis of prostate cancer cells in vivo. Conclusions: Our study provides evidence that Gal-1 is an important target for mCRPC therapy, and LLS30 is a promising small-molecule compound that can potentially overcome mCRPC. © 2018 American Association for Cancer Research.

U2 - 10.1158/1078-0432.CCR-18-0157

DO - 10.1158/1078-0432.CCR-18-0157

M3 - Article

VL - 24

SP - 4319

EP - 4331

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 17

ER -