Abstract：Objective To study the role and mechanism of hypoxia in Erastin-induced iron death of pancreatic ductal adeno carcinoma (PDAC) cells. Methods PDAC cells were divided into four groups, normoxia DMSO group, normoxia Erastin group (5.0 μmol/L Erastin solution), hypoxia DMSO group, and hypoxia Erastin group (5.0 μmol/L Erastin solution). After 72 hours of incubation, the cell activity was detected by CCK-8 method; full-wavelength microplate reader detects the content of reduced glutathione (GSH) and malondialdehyde (MDA); RT-qPCR detected the expression level of the deacetylase Sirtuin3 (SIRT3) mRNA; animal subcutaneous tumor formation experiments were used to detect the effects of hypoxia on iron death in vivo. Results The PANC1 cell activity, the relative content of reduced GSH, and the relative expression of SIRT3 mRNA in the hypoxic Erastin group were higher than those of the normoxic Erastin group, and the differences were statistically significant (P ＜ 0.05). The relative content of MDA in the hypoxic Erastin group was lower than that of the normoxic Erastin group (P ＜ 0.05). The tumor volume of the normoxic Erastin group was smaller than that of the normoxic DMSO group, and the difference was statistically significant (P ＜ 0.05). There was no significant difference in tumor volume between the hypoxic Erastin group and the hypoxic DMSO group (P ＞ 0.05). Conclusion Hypoxia inhibits the iron death of PDAC induced by Erastin, and the increased expression of SIRT3 is one of its mechanisms.
高钦玥1 宋廉1 吴琪炜1 魏士杰1 刘赛1 龚爱华2 朱海涛1 王冬青1. 低氧在Erastin诱导的胰腺导管腺癌细胞铁死亡中的作用及其机制[J]. 中国医药导报, 2021, 18(18): 22-25,39.
GAO Qinyue1 SONG Lian1 Wu Qiwei1 WEI Shijie1 LIU Sai1 GONG Aihua2 ZHU Haitao1 WANG Dongqing1. The role and mechanism of hypoxia in Erastin-induced ferroptosis of pancreatic ductal adenocarcinoma cells. 中国医药导报, 2021, 18(18): 22-25,39.
[1] Dixon SJ，Lemberg KM，Lamprecht MR，et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death [J]. Cell，2012，149（5）：1060-1072.
[2] Stockwell BR，Jiang X，Gu W. Emerging Mechanisms and Disease Relevance of Ferroptosis [J]. Trends Cell Biol，2020， 30（6）：478-490.
[3] Bersuker K，Hendricks JM，Li Z，et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis [J]. Nature，2019，575（7784）：688-692.
[4] Seibt TM，Proneth B，Conrad M. Role of GPX4 in ferroptosis and its pharmacological implication [J]. Free Radic Biol Med，2019，133：144-152.
[5] Stockwell BR，Jiang X. The Chemistry and Biology of Ferroptosis [J]. Cell Chem Biol，2020，27（4）：365-375.
[6] Yang Y，Luo M，Zhang K，et al. Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma [J]. Nat Commun，2020，11（1）：433.
[7] Wu Z，Geng Y，Lu X，et al. Chaperone-mediated autophagy is involved in the execution of ferroptosis [J]. Proc Natl Acad Sci U S A，2019，116（8）：2996-3005.
[8] Hirschhorn T，Stockwell BR. The development of the concept of ferroptosis [J]. Free Radic Biol Med，2019，133：130-143.
[9] Yagoda N，von Rechenberg M，Zaganjor E，et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels [J]. Nature，2007，447（7146）：864-868.
[10] Badgley MA，Kremer DM，Maurer HC，et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice [J]. Science，2020，368（6486）：85-89.
[11] Yu L，Teoh ST，Ensink E，et al. Cysteine catabolism and the serine biosynthesis pathway support pyruvate production during pyruvate kinase knockdown in pancreatic cancer cells [J]. Cancer Metab，2019，7：13.
[12] Abdalla MY，Ahmad IM，Rachagani S，et al. Enhancing responsiveness of pancreatic cancer cells to gemcitabine treatment under hypoxia by heme oxygenase-1 inhibition [J]. Transl Res，2019，207：56-69.
[13] Yamasaki A，Yanai K，Onishi H. Hypoxia and pancreatic ductal adenocarcinoma [J]. Cancer Lett，2020，484：9-15.
[14] Yang M，Chen P，Liu J，et al. Clockophagy is a novel selective autophagy process favoring ferroptosis [J]. Sci Adv，2019，5（7）：eaaw2238.
[15] Lee H，Zandkarimi F，Zhang Y，et al. Energy-stress-mediated AMPK activation inhibits ferroptosis [J]. Nat Cell Biol，2020，22（2）：225-234.
[16] Chu B，Kon N，Chen D，et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway [J]. Nat Cell Biol，2019，21（5）：579-591.
[17] Hassannia B，Vandenabeele P，Vanden Berghe T. Targeting Ferroptosis to Iron Out Cancer [J]. Cancer Cell，2019，35（6）：830-849.
[18] Gao M，Yi J，Zhu J，et al. Role of Mitochondria in Ferroptosis [J]. Mol Cell，2019，73（2）：354-363.
[19] Bock FJ，Tait SWG. Mitochondria as multifaceted regulators of cell death [J]. Nat Rev Mol Cell Biol，2020，21（2）：85-100.
[20] Zhang X，Ji R，Liao X，et al. MicroRNA-195 Regulates Metabolism in Failing Myocardium Via Alterations in Sirtuin 3 Expression and Mitochondrial Protein Acetylation [J]. Circulation，2018，137（19）：2052-2067.
[21] Gao J，Feng Z，Wang X，et al. SIRT3/SOD2 maintains osteoblast differentiation and bone formation by regulating mitochondrial stress [J]. Cell Death Differ，2018，25（2）：229-240.
[22] Semenza GL. Hypoxia-inducible factors in physiology and medicine [J]. Cell，2012，148（3）：399-408.
[23] Yu L，Hales CA. Long-term exposure to hypoxia inhibits tumor progression of lung cancer in rats and mice [J]. BMC Cancer，2011，11：331.
[24] Liang D，Ma Y，Liu J，et al. The hypoxic microenvironment upgrades stem-like properties of ovarian cancer cells [J]. BMC Cancer，2012，12：201.
[25] Byrne MB，Leslie MT，Gaskins HR，et al. Methods to study the tumor microenvironment under controlled oxygen conditions [J]. Trends Biotechnol，2014，32（11）：556-563.
京公网安备 11010502046598号