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TIGAR knockdown enhanced the anticancer effect of aescin via regulating autophagy and apoptosis in colorectal cancer cells.
Acta Pharmacol Sin. 2019 Jan; 40(1):111-121.AP

Abstract

Our previous study showed that TP53-induced glycolysis and apoptosis regulator (TIGAR) regulated ROS, autophagy, and apoptosis in response to hypoxia and chemotherapeutic drugs. Aescin, a triterpene saponin, exerts anticancer effects and increases ROS levels. The ROS is a key upstream signaling to activate autophagy. Whether there is a crosstalk between TIGAR and aescin in regulating ROS, autophagy, and apoptosis is unknown. In this study, we found that aescin inhibited cell viability and colony formation, and induced DNA damage, cell cycle arrest, and apoptosis in cancer cell lines HCT-116 and HCT-8 cells. Concurrently, aescin increased the expression of TIGAR, ROS levels, and autophagy activation. Knockdown of TIGAR enhanced the anticancer effects of aescin in vitro and in vivo, whereas overexpression of TIGAR or replenishing TIGAR downstream products, NADPH and ribose, attenuated aescin-induced apoptosis. Furthermore, aescin-induced ROS elevation and autophagy activation were further strengthened by TIGAR knockdown in HCT-116 cells. However, autophagy inhibition by knockdown of autophagy-related gene ATG5 or 3-methyladenine (3-MA) exaggerated aescin-induced apoptosis when TIGAR was knocked down. In conclusion, TIGAR plays a dual role in determining cancer cell fate via inhibiting both apoptosis and autophagy in response to aescin, which indicated that inhibition of TIGAR and/or autophagy may be a junctional therapeutic target in treatment of cancers with aescin.

Authors+Show Affiliations

Department of Vascular Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215007, China. Department of General Surgery, The First People's Hospital of Wu Jiang, Suzhou, 215200, China. Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215007, China.Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215007, China.Department of General Surgery, The First People's Hospital of Wu Jiang, Suzhou, 215200, China.Department of General Surgery, The First People's Hospital of Wu Jiang, Suzhou, 215200, China.Department of General Surgery, The First People's Hospital of Wu Jiang, Suzhou, 215200, China.Department of General Surgery, The First People's Hospital of Wu Jiang, Suzhou, 215200, China.Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.Department of General Surgery, The First People's Hospital of Wu Jiang, Suzhou, 215200, China. wjsgh3026@sina.com.Department of Vascular Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215007, China. flytsg@126.com.Department of General Surgery, The First People's Hospital of Wu Jiang, Suzhou, 215200, China. wjyygqg@sohu.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29769743

Citation

Li, Bin, et al. "TIGAR Knockdown Enhanced the Anticancer Effect of Aescin Via Regulating Autophagy and Apoptosis in Colorectal Cancer Cells." Acta Pharmacologica Sinica, vol. 40, no. 1, 2019, pp. 111-121.
Li B, Wang Z, Xie JM, et al. TIGAR knockdown enhanced the anticancer effect of aescin via regulating autophagy and apoptosis in colorectal cancer cells. Acta Pharmacol Sin. 2019;40(1):111-121.
Li, B., Wang, Z., Xie, J. M., Wang, G., Qian, L. Q., Guan, X. M., Shen, X. P., Qin, Z. H., Shen, G. H., Li, X. Q., & Gao, Q. G. (2019). TIGAR knockdown enhanced the anticancer effect of aescin via regulating autophagy and apoptosis in colorectal cancer cells. Acta Pharmacologica Sinica, 40(1), 111-121. https://doi.org/10.1038/s41401-018-0001-2
Li B, et al. TIGAR Knockdown Enhanced the Anticancer Effect of Aescin Via Regulating Autophagy and Apoptosis in Colorectal Cancer Cells. Acta Pharmacol Sin. 2019;40(1):111-121. PubMed PMID: 29769743.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TIGAR knockdown enhanced the anticancer effect of aescin via regulating autophagy and apoptosis in colorectal cancer cells. AU - Li,Bin, AU - Wang,Zhong, AU - Xie,Jia-Ming, AU - Wang,Gang, AU - Qian,Li-Qiang, AU - Guan,Xue-Mei, AU - Shen,Xue-Ping, AU - Qin,Zheng-Hong, AU - Shen,Gen-Hai, AU - Li,Xiao-Qiang, AU - Gao,Quan-Gen, Y1 - 2018/05/16/ PY - 2017/10/08/received PY - 2018/01/15/accepted PY - 2018/5/18/pubmed PY - 2019/3/27/medline PY - 2018/5/18/entrez KW - TIGAR KW - aescin KW - apoptosis KW - autophagy KW - colorectal cancer SP - 111 EP - 121 JF - Acta pharmacologica Sinica JO - Acta Pharmacol. Sin. VL - 40 IS - 1 N2 - Our previous study showed that TP53-induced glycolysis and apoptosis regulator (TIGAR) regulated ROS, autophagy, and apoptosis in response to hypoxia and chemotherapeutic drugs. Aescin, a triterpene saponin, exerts anticancer effects and increases ROS levels. The ROS is a key upstream signaling to activate autophagy. Whether there is a crosstalk between TIGAR and aescin in regulating ROS, autophagy, and apoptosis is unknown. In this study, we found that aescin inhibited cell viability and colony formation, and induced DNA damage, cell cycle arrest, and apoptosis in cancer cell lines HCT-116 and HCT-8 cells. Concurrently, aescin increased the expression of TIGAR, ROS levels, and autophagy activation. Knockdown of TIGAR enhanced the anticancer effects of aescin in vitro and in vivo, whereas overexpression of TIGAR or replenishing TIGAR downstream products, NADPH and ribose, attenuated aescin-induced apoptosis. Furthermore, aescin-induced ROS elevation and autophagy activation were further strengthened by TIGAR knockdown in HCT-116 cells. However, autophagy inhibition by knockdown of autophagy-related gene ATG5 or 3-methyladenine (3-MA) exaggerated aescin-induced apoptosis when TIGAR was knocked down. In conclusion, TIGAR plays a dual role in determining cancer cell fate via inhibiting both apoptosis and autophagy in response to aescin, which indicated that inhibition of TIGAR and/or autophagy may be a junctional therapeutic target in treatment of cancers with aescin. SN - 1745-7254 UR - https://www.unboundmedicine.com/medline/citation/29769743/TIGAR_knockdown_enhanced_the_anticancer_effect_of_aescin_via_regulating_autophagy_and_apoptosis_in_colorectal_cancer_cells_ L2 - http://dx.doi.org/10.1038/s41401-018-0001-2 DB - PRIME DP - Unbound Medicine ER -