Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/92207
標題: 薑黃素促進縫隙連接蛋白降解與temozolomide誘發膠質瘤細胞死亡
Curcumin promotes connexin43 degradation and temozolomide-induced glioma cell death
作者: 陳俊全
CHUN-CHUAN CHEN
關鍵字: 多形性膠質母細胞瘤;帝盟多;縫隙連接蛋白;薑黃素;glioblastoma multiforme;temozolomide;connexin43;curcumin
引用: Ableser, M. J., Penuela, S., Lee, J., Shao, Q., and Laird, D. W. (2014). Connexin43 reduces melanoma growth within a keratinocyte microenvironment and during tumorigenesis in vivo. The Journal of biological chemistry 289, 1592-1603. Aggarwal, B. B., Banerjee, S., Bharadwaj, U., Sung, B., Shishodia, S., and Sethi, G. (2007a). Curcumin induces the degradation of cyclin E expression through ubiquitin-dependent pathway and up-regulates cyclin-dependent kinase inhibitors p21 and p27 in multiple human tumor cell lines. Biochemical pharmacology 73, 1024-1032. Aggarwal, B. B., Sundaram, C., Malani, N., and Ichikawa, H. (2007b). Curcumin: the Indian solid gold. Advances in experimental medicine and biology 595, 1-75. Ambegaokar, S. S., Wu, L., Alamshahi, K., Lau, J., Jazayeri, L., Chan, S., Khanna, P., Hsieh, E., and Timiras, P. S. (2003). Curcumin inhibits dose-dependently and time-dependently neuroglial cell proliferation and growth. Neuro endocrinology letters 24, 469-473. Anand, P., Sundaram, C., Jhurani, S., Kunnumakkara, A. B., and Aggarwal, B. B. (2008). Curcumin and cancer: an 'old-age' disease with an 'age-old' solution. Cancer letters 267, 133-164. Aoki, H., Takada, Y., Kondo, S., Sawaya, R., Aggarwal, B. B., and Kondo, Y. (2007). Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Molecular pharmacology 72, 29-39. Barth, A. I., Nathke, I. S., and Nelson, W. J. (1997). Cadherins, catenins and APC protein: interplay between cytoskeletal complexes and signaling pathways. Current opinion in cell biology 9, 683-690. Behrens, J., Mareel, M. M., Van Roy, F. M., and Birchmeier, W. (1989). Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. The Journal of cell biology 108, 2435-2447. Belkaid, A., Copland, I. B., Massillon, D., and Annabi, B. (2006). Silencing of the human microsomal glucose-6-phosphate translocase induces glioma cell death: potential new anticancer target for curcumin. FEBS letters 580, 3746-3752. Berx, G., and Van Roy, F. (2001). The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression. Breast cancer research : BCR 3, 289-293. Bier, A., Oviedo-Landaverde, I., Zhao, J., Mamane, Y., Kandouz, M., and Batist, G. (2009). Connexin43 pseudogene in breast cancer cells offers a novel therapeutic target. Molecular cancer therapeutics 8, 786-793. Buckner, J. C., Brown, P. D., O'Neill, B. P., Meyer, F. B., Wetmore, C. J., and Uhm, J. H. (2007). Central nervous system tumors. Mayo Clinic proceedings 82, 1271-1286. Cesen-Cummings, K., Fernstrom, M. J., Malkinson, A. M., and Ruch, R. J. (1998). Frequent reduction of gap junctional intercellular communication and connexin43 expression in human and mouse lung carcinoma cells. Carcinogenesis 19, 61-67. Clairmont, A., and Sies, H. (1997). Evidence for a posttranscriptional effect of retinoic acid on connexin43 gene expression via the 3'-untranslated region. FEBS letters 419, 268-270. Caltabiano, R., Torrisi, A., Condorelli, D., Albanese, V., and Lanzafame, S. (2010). High levels of connexin 43 mRNA in high grade astrocytomas. Study of 32 cases with in situ hybridization. Acta histochemica 112, 529-535. Crespin, S., Bechberger, J., Mesnil, M., Naus, C. C., and Sin, W. C. (2010). The carboxy-terminal tail of connexin43 gap junction protein is sufficient to mediate cytoskeleton changes in human glioma cells. Journal of cellular biochemistry 110, 589-597 Chang, W. W., Lai, C. H., Chen, M. C., Liu, C. F., Kuan, Y. D., Lin, S. T., and Lee, C. H. (2013). Salmonella enhance chemosensitivity in tumor through connexin 43 upregulation. International journal of cancer Journal international du cancer 133, 1926-1935. Chen, C. C., Taniguchi, T., and D'Andrea, A. (2007). The Fanconi anemia (FA) pathway confers glioma resistance to DNA alkylating agents. Journal of molecular medicine 85, 497-509. Chipman, J. K., Mally, A., and Edwards, G. O. (2003). Disruption of gap junctions in toxicity and carcinogenicity. Toxicological sciences : an official journal of the Society of Toxicology 71, 146-153. Crespin, S., Bechberger, J., Mesnil, M., Naus, C. C., and Sin, W. C. (2010). The carboxy-terminal tail of connexin43 gap junction protein is sufficient to mediate cytoskeleton changes in human glioma cells. Journal of cellular biochemistry 110, 589-597. Dhandapani, K. M., Mahesh, V. B., and Brann, D. W. (2007). Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFkappaB transcription factors. Journal of neurochemistry 102, 522-538. Fukushima, T., Takeshima, H., and Kataoka, H. (2009). Anti-glioma therapy with temozolomide and status of the DNA-repair gene MGMT. Anticancer research 29, 4845-4854. Gao, X., Deeb, D., Jiang, H., Liu, Y. B., Dulchavsky, S. A., and Gautam, S. C. (2005). Curcumin differentially sensitizes malignant glioma cells to TRAIL/Apo2L-mediated apoptosis through activation of procaspases and release of cytochrome c from mitochondria. Journal of experimental therapeutics & oncology 5, 39-48. Gerson, S. L. (2002). Clinical relevance of MGMT in the treatment of cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20, 2388-2399. Goel, A., Kunnumakkara, A. B., and Aggarwal, B. B. (2008). Curcumin as 'Curecumin': from kitchen to clinic. Biochemical pharmacology 75, 787-809. Goldberg, G. S., Moreno, A. P., and Lampe, P. D. (2002). Gap junctions between cells expressing connexin 43 or 32 show inverse permselectivity to adenosine and ATP. The Journal of biological chemistry 277, 36725-36730. Griscelli, F., Li, H., Cheong, C., Opolon, P., Bennaceur-Griscelli, A., Vassal, G., Soria, J., Soria, C., Lu, H., Perricaudet, M., and Yeh, P. (2000). Combined effects of radiotherapy and angiostatin gene therapy in glioma tumor model. Proceedings of the National Academy of Sciences of the United States of America 97, 6698-6703. Hattori, Y., Fukushima, M., and Maitani, Y. (2007). Non-viral delivery of the connexin 43 gene with histone deacetylase inhibitor to human nasopharyngeal tumor cells enhances gene expression and inhibits in vivo tumor growth. International journal of oncology 30, 1427-1439 Hammond, L. A., Eckardt, J. R., Baker, S. D., Eckhardt, S. G., Dugan, M., Forral, K., Reidenberg, P., Statkevich, P., Weiss, G. R., Rinaldi, D. A., et al. (1999). Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 17, 2604-2613. Harvey, A. L. (2008). Natural products in drug discovery. Drug discovery today 13, 894-901. Hatcher, H., Planalp, R., Cho, J., Torti, F. M., and Torti, S. V. (2008). Curcumin: from ancient medicine to current clinical trials. Cellular and molecular life sciences : CMLS 65, 1631-1652. Hill, C. I., Nixon, C. S., Ruehmeier, J. L., and Wolf, L. M. (2002). Brain tumors. Physical therapy 82, 496-502. Huang, R. P., Hossain, M. Z., Sehgal, A., and Boynton, A. L. (1999). Reduced connexin43 expression in high-grade human brain glioma cells. Journal of surgical oncology 70, 21-24. Huang, T., Zhu, Y., Fang, X., Chi, Y., Kitamura, M., and Yao, J. (2010). Gap junctions sensitize cancer cells to proteasome inhibitor MG132-induced apoptosis. Cancer science 101, 713-721. Huse, J. T., and Holland, E. C. (2010). Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nature reviews Cancer 10, 319-331. Huang, R., Lin, Y., Wang, C. C., Gano, J., Lin, B., Shi, Q., Boynton, A., Burke, J., and Huang, R. P. (2002). Connexin 43 suppresses human glioblastoma cell growth by down-regulation of monocyte chemotactic protein 1, as discovered using protein array technology. Cancer research 62, 2806-2812 Imamdi, R., de Graauw, M., and van de Water, B. (2004). Protein kinase C mediates cisplatin-induced loss of adherens junctions followed by apoptosis of renal proximal tubular epithelial cells. The Journal of pharmacology and experimental therapeutics 311, 892-903. Ionta, M., Ferreira, R. A., Pfister, S. C., and Machado-Santelli, G. M. (2009). Exogenous Cx43 expression decrease cell proliferation rate in rat hepatocarcinoma cells independently of functional gap junction. Cancer cell international 9, 22. Jamora, C., and Fuchs, E. (2002). Intercellular adhesion, signalling and the cytoskeleton. Nature cell biology 4, E101-108. Jongen, W. M., Fitzgerald, D. J., Asamoto, M., Piccoli, C., Slaga, T. J., Gros, D., Takeichi, M., and Yamasaki, H. (1991). Regulation of connexin 43-mediated gap junctional intercellular communication by Ca2+ in mouse epidermal cells is controlled by E-cadherin. The Journal of cell biology 114, 545-555. Kang, S. K., Cha, S. H., and Jeon, H. G. (2006). Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells. Stem cells and development 15, 165-174. Karmakar, S., Banik, N. L., Patel, S. J., and Ray, S. K. (2006). Curcumin activated both receptor-mediated and mitochondria-mediated proteolytic pathways for apoptosis in human glioblastoma T98G cells. Neuroscience letters 407, 53-58. Karmakar, S., Banik, N. L., and Ray, S. K. (2007). Curcumin suppressed anti-apoptotic signals and activated cysteine proteases for apoptosis in human malignant glioblastoma U87MG cells. Neurochemical research 32, 2103-2113. Kijima, H., and Ueyama, Y. (2003). [Molecular mechanism of drug resistance in colorectal cancer]. Nihon rinsho Japanese journal of clinical medicine 61 Suppl 7, 303-309. Kim, S. Y., Jung, S. H., and Kim, H. S. (2005). Curcumin is a potent broad spectrum inhibitor of matrix metalloproteinase gene expression in human astroglioma cells. Biochemical and biophysical research communications 337, 510-516. Laing, J. G., and Beyer, E. C. (1995). The gap junction protein connexin43 is degraded via the ubiquitin proteasome pathway. The Journal of biological chemistry 270, 26399-26403. Laird, D. W., Fistouris, P., Batist, G., Alpert, L., Huynh, H. T., Carystinos, G. D., and Alaoui-Jamali, M. A. (1999). Deficiency of connexin43 gap junctions is an independent marker for breast tumors. Cancer research 59, 4104-4110. Lamoral-Theys, D., Pottier, L., Dufrasne, F., Neve, J., Dubois, J., Kornienko, A., Kiss, R., and Ingrassia, L. (2010). Natural polyphenols that display anticancer properties through inhibition of kinase activity. Current medicinal chemistry 17, 812-825. Lau, A. F., Kanemitsu, M. Y., Kurata, W. E., Danesh, S., and Boynton, A. L. (1992). Epidermal growth factor disrupts gap-junctional communication and induces phosphorylation of connexin43 on serine. Molecular biology of the cell 3, 865-874. Lefranc, F., Brotchi, J., and Kiss, R. (2005). Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23, 2411-2422. Liao, C. K., Jeng, C. J., Wang, H. S., Wang, S. H., and Wu, J. C. (2013). Lipopolysaccharide induces degradation of connexin43 in rat astrocytes via the ubiquitin-proteasome proteolytic pathway. PloS one 8, e79350. Lu, J. J., Cai, Y. J., and Ding, J. (2012). The short-time treatment with curcumin sufficiently decreases cell viability, induces apoptosis and copper enhances these effects in multidrug-resistant K562/A02 cells. Molecular and cellular biochemistry 360, 253-260. Martins-Marques, T., Catarino, S., Zuzarte, M., Marques, C., Matafome, P., Pereira, P., and Girao, H. (2015). Ischaemia-induced autophagy leads to degradation of gap junction protein connexin43 in cardiomyocytes. The Biochemical journal 467, 231-245. Meyer, R. A., Laird, D. W., Revel, J. P., and Johnson, R. G. (1992). Inhibition of gap junction and adherens junction assembly by connexin and A-CAM antibodies. The Journal of cell biology 119, 179-189. Middlemas, D. S., Stewart, C. F., Kirstein, M. N., Poquette, C., Friedman, H. S., Houghton, P. J., and Brent, T. P. (2000). Biochemical correlates of temozolomide sensitivity in pediatric solid tumor xenograft models. Clinical cancer research : an official journal of the American Association for Cancer Research 6, 998-1007. Mukherjee, P. K., and Wahile, A. (2006). Integrated approaches towards drug development from Ayurveda and other Indian system of medicines. Journal of ethnopharmacology 103, 25-35. Murray, S. A., Davis, K., Fishman, L. M., and Bornstein, S. R. (2000). Alpha1 connexin 43 gap junctions are decreased in human adrenocortical tumors. The Journal of clinical endocrinology and metabolism 85, 890-895. Munoz, J. L., Rodriguez-Cruz, V., Greco, S. J., Ramkissoon, S. H., Ligon, K. L., and Rameshwar, P. (2014). Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43. Cell death & disease 5, e1145. Naus, C. C., and Laird, D. W. (2010). Implications and challenges of connexin connections to cancer. Nature reviews Cancer 10, 435-441. Nagai, S., Kurimoto, M., Washiyama, K., Hirashima, Y., Kumanishi, T., and Endo, S. (2005). Inhibition of cellular proliferation and induction of apoptosis by curcumin in human malignant astrocytoma cell lines. Journal of neuro-oncology 74, 105-111. Neijssen, J., Herberts, C., Drijfhout, J. W., Reits, E., Janssen, L., and Neefjes, J. (2005). Cross-presentation by intercellular peptide transfer through gap junctions. Nature 434, 83-88. Newlands, E. S., Stevens, M. F., Wedge, S. R., Wheelhouse, R. T., and Brock, C. (1997). Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer treatment reviews 23, 35-61. Newman, D. J., Cragg, G. M., and Snader, K. M. (2003). Natural products as sources of new drugs over the period 1981-2002. Journal of natural products 66, 1022-1037. Ohgaki, H., and Kleihues, P. (2005). Epidemiology and etiology of gliomas. Acta neuropathologica 109, 93-108. Patil, R., Portilla-Arias, J., Ding, H., Inoue, S., Konda, B., Hu, J., Wawrowsky, K. A., Shin, P. K., Black, K. L., Holler, E., and Ljubimova, J. Y. (2010). Temozolomide delivery to tumor cells by a multifunctional nano vehicle based on poly(beta-L-malic acid). Pharmaceutical research 27, 2317-2329. Prasad, S., and Aggarwal, B. B. (2011). Turmeric, the Golden Spice: From Traditional Medicine to Modern Medicine. In Herbal Medicine: Biomolecular and Clinical Aspects, I.F.F. Benzie, and S. Wachtel-Galor, eds. (Boca Raton (FL)). Pu, P., Xia, Z., Yu, S., and Huang, Q. (2004). Altered expression of Cx43 in astrocytic tumors. Clinical neurology and neurosurgery 107, 49-54. Qu, Y., and Dahl, G. (2002). Function of the voltage gate of gap junction channels: selective exclusion of molecules. Proceedings of the National Academy of Sciences of the United States of America 99, 697-702. Rackauskas, M., Neverauskas, V., and Skeberdis, V. A. (2010). Diversity and properties of connexin gap junction channels. Medicina 46, 1-12. Ramachandran, C., Nair, S. M., Escalon, E., and Melnick, S. J. (2012). Potentiation of etoposide and temozolomide cytotoxicity by curcumin and turmeric force in brain tumor cell lines. Journal of complementary & integrative medicine 9, Article 20. Reardon, D. A., Desjardins, A., Peters, K., Gururangan, S., Sampson, J., Rich, J. N., McLendon, R., Herndon, J. E., 2nd, Marcello, J., Threatt, S., et al. (2011). Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. Journal of neuro-oncology 103, 371-379. Rhee, D. J., Kong, D. S., Kim, W. S., Park, K. B., Lee, J. I., Suh, Y. L., Song, S. Y., Kim, S. T., Lim, D. H., Park, K., et al. (2009). Efficacy of temozolomide as adjuvant chemotherapy after postsurgical radiotherapy alone for glioblastomas. Clinical neurology and neurosurgery 111, 748-751. Ringertz, N. (1950). Grading of gliomas. Acta pathologica et microbiologica Scandinavica 27, 51-64. Robe, P. A., Rogister, B., Merville, M. P., and Bours, V. (2000). Growth regulation of astrocytes and C6 cells by TGFbeta1: correlation with gap junctions. Neuroreport 11, 2837-2841. Shah, S. N., Hile, S. E., and Eckert, K. A. (2010). Defective mismatch repair, microsatellite mutation bias, and variability in clinical cancer phenotypes. Cancer research 70, 431-435. Sharom, F. J. (2008). ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics 9, 105-127. Shinojima, N., Yokoyama, T., Kondo, Y., and Kondo, S. (2007). Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy 3, 635-637. Sin, W. C., Bechberger, J. F., Rushlow, W. J., and Naus, C. C. (2008). Dose-dependent differential upregulation of CCN1/Cyr61 and CCN3/NOV by the gap junction protein Connexin43 in glioma cells. Journal of cellular biochemistry 103, 1772-1782. Sin, W. C., Crespin, S., and Mesnil, M. (2012). Opposing roles of connexin43 in glioma progression. Biochimica et biophysica acta 1818, 2058-2067. Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J., Belanger, K., Brandes, A. A., Marosi, C., Bogdahn, U., et al. (2005). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England journal of medicine 352, 987-996. Tate, A. W., Lung, T., Radhakrishnan, A., Lim, S. D., Lin, X., and Edlund, M. (2006). Changes in gap junctional connexin isoforms during prostate cancer progression. The Prostate 66, 19-31. Wang, C., Zhang, X., Teng, Z., Zhang, T., and Li, Y. (2014). Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice. European journal of pharmacology 740, 312-320. Wang, M., Berthoud, V. M., and Beyer, E. C. (2007). Connexin43 increases the sensitivity of prostate cancer cells to TNFalpha-induced apoptosis. Journal of cell science 120, 320-329. Woo, M. S., Jung, S. H., Kim, S. Y., Hyun, J. W., Ko, K. H., Kim, W. K., and Kim, H. S. (2005). Curcumin suppresses phorbol ester-induced matrix metalloproteinase-9 expression by inhibiting the PKC to MAPK signaling pathways in human astroglioma cells. Biochemical and biophysical research communications 335, 1017-1025. Yin, H., Zhou, Y., Wen, C., Zhou, C., Zhang, W., Hu, X., Wang, L., You, C., and Shao, J. (2014). Curcumin sensitizes glioblastoma to temozolomide by simultaneously generating ROS and disrupting AKT/mTOR signaling. Oncology reports 32, 1610-1616. Zhang, W., DeMattia, J. A., Song, H., and Couldwell, W. T. (2003). Communication between malignant glioma cells and vascular endothelial cells through gap junctions. Journal of neurosurgery 98, 846-853. Zhou, H., Beevers, C. S., and Huang, S. (2011). The targets of curcumin. Current drug targets 12, 332-347.
摘要: 
多形性膠質母細胞瘤 (glioblastoma multiforme; GBM)屬grade Ⅳ的星狀細胞瘤,為成年人中最惡性的原發性腦瘤,浸潤性高且轉移快速之腦癌。Temozolomide (TMZ)為目前臨床上治療GBM第一線藥物,經抑制DNA 複製而誘發癌細胞死亡,但長期使用TMZ會導致抗藥性之產生。過去研究結果顯示,長期施予TMZ治療GBM易引起connexin43 (Cx43)表現量增加,可能為TMZ造成抗藥性之原因。故本研究欲探討長期給予TMZ治療膠質細胞瘤的抗藥性機制。SRB assay研究結果顯示,給予resistant GBM TMZ藥物治療後,對藥物的感受性降低。Western blot結果顯示resistant GBM的ATP-binding cassette transporters (ABC transporters)相關蛋白不受影響,而是Cx43蛋白表現量明顯增加。隨著給予curcumin濃度與時間增加促使Cx43表現量隨之減少且不影響其他connexin家族蛋白如Cx26與Cx30的表現量,以及EMT (epithelial-mesenchymal transition)相關蛋白如α E-catenin、β-catenin與E-cadherin的表現量。利用SRB和flow cytometer檢測細胞存活情形,結果顯示合併curcumin及TMZ治療GBM後誘發細胞死亡及凋亡現象。Real-time PCR結果顯示curcumin並不影響Cx43 mRNA的表現量,由此發現Cx43蛋白降解可能為轉譯後修飾機制。因此利用translation inhibitor cycloheximide (CHX) 觀察到更促進Cx43的降解,然而給予autophagy inhibitor 3-Methyladenine (3MA) 並沒恢復Cx43的表現量。更重要利用proteasome inhibitor carbobenzoxy-Leu-Leu-leucinal (MG132) 觀察到逆轉curcumin-induced Cx43降解情形。最後合併curcumin和TMZ治療resistant GBM,結果顯示確實造成細胞死亡。因此,Cx43可能為未來治療腦癌之新策略。

Glioblastoma Multiforme (GBM), the most common adult primary brain tumor, has poor prognosis with < 3% survival after 5 years of diagnosis. Currently, anti-neoplastic treatment combines chemotherapy, temozolomide (TMZ), radiotherapy and resectional surgery. TMZ is an alkylating agent that induces apoptosis through DNA strand breaks is considered as the frontline chemotherapeutic agent for GBM. Despite its frontline status, GBM patients commonly exhibit resistance to TMZ treatment. Therefore, current study intends to investigate the resistant mechanism underlying long term TMZ-treatment GBM. SRB assay showed that GBM cells exhibit resistance to TMZ treatment. Western blot showed that connexin43 overexpression in resistant GBM cells and did not affect the ATP-binding cassette transporters (ABC transporters) expression. Further suggested that curcumin significantly reduced connexin43 protein expressions in time and dosage dependent manners. Furtheremore, curcumin did not affect connexin26, β-catenin, α E-catenin expressions in human GBM. Combined treatment of curcumin and TMZ promotes cell death and apoptosis using SRB assay and flow cytometry. Interestingly, curcumin did not affect connexin43 mRNA expression in human GBM cells. This reaction appears to be mediated by a post-translational modification mechanism. However, treatment with translation inhibitor cycloheximide (CHX) exerts an additional effects of connexin43 degradation. Treatment with autophagy inhibitor 3-Methyladenine (3MA) did not reverse curcumin-induced connexin43 degradation. Importantly, treatment with a proteasome inhibitor carbobenzoxy-Leu-Leu-leucinal (MG132) significantly reversed curcumin-induced connexin43 degradation. Our results suggest that curcumin induces connexin43 degradation through the ubiquitin-proteasome pathway. Current findings suggest that combined treatment of curcumin and TMZ significantly increases resistant GBM cell death and connexin43 can be a potential therapeutic candidate for the treatment of brain cancer.
URI: http://hdl.handle.net/11455/92207
Rights: 不同意授權瀏覽/列印電子全文服務
Appears in Collections:生物化學研究所

Files in This Item:
File SizeFormat Existing users please Login
nchu-104-7101058012-1.pdf1.38 MBAdobe PDFThis file is only available in the university internal network    Request a copy
Show full item record
 

Google ScholarTM

Check


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.