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.
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Acknowledgements
This work was supported by grants from National Natural Science Foundation of China (No. 81770483 and 81602613), Jiangsu Provincial Commission of Health and Family Planning (No. YG201402 and YG201503), Jiangsu Provincial Medical Youth Talent (No. QNRC2016249), Jiangsu Provincial Science and Technology office (No. BL2014043), Suzhou Science and Technology Bureau (No. SYSD2013041, SYSD2016044, SYSD2017041, and SYS201788), Suzhou Health and Family Planning Commission Program (No. LCZX201504), Wujiang District Science and Technology Bureau (No. WS201301), and Wujiang District Commission of Health and Family Planning (No. WWK201607 and WWK201609).
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All listed authors contributed to the idea generation, design, and completion of this study. B.L., Z.W., and J.-M.X. contributed equally to the idea generation, experimental work, and manuscript preparation; G.W., L.-Q.Q., X.-M.G., and X.-P.S. contributed to the experimental work and manuscript preparation; X.-Q.L., Q.-G.G., G.-H.S., and Z.-H.Q. guided the idea generation, experimental work, and manuscript preparation. All authors reviewed the manuscript.
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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 40, 111–121 (2019). https://doi.org/10.1038/s41401-018-0001-2
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DOI: https://doi.org/10.1038/s41401-018-0001-2
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