The STAT-ROS cycle extends IFN‑induced cancer cell apoptosis

Wang,Yan; Yu,Xiaoyu; Song,Hongtao; Feng,Di; Jiang,Yang; Wu,Shuang; Geng,Jingshu

doi:10.3892/ijo.2017.4196

The STAT-ROS cycle extends IFN‑induced cancer cell apoptosis

Authors:
- Yan Wang
- Xiaoyu Yu
- Hongtao Song
- Di Feng
- Yang Jiang
- Shuang Wu
- Jingshu Geng
View Affiliations

Affiliations: Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, P.R. China
Published online on: November 8, 2017 https://doi.org/10.3892/ijo.2017.4196
Pages: 305-313

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

In mammals, the signal transducer and activator of transcription (STAT) protein processes mitochondria importation targets and mitochondria respiratory complexes, and triggers reactive oxygen species (ROS) generation, which conversely rapidly initiates the activation of STAT. Interferon (IFN) administration increases cancer cell apoptosis via STAT activation and ROS accumulation. However, the existence of a STAT-ROS cycle and how it affects IFN‑induced cancer cellular apoptosis are unclear. In the present study, we used MCF7 breast cancer cells and confirmed that a combination of IFN‑α/β/γ incubation induced STAT1/3 phosphorylation and mitochondria importation, which increased mitochondria respiratory complexes, the cellular oxygen consumption rate (OCR), and ROS production, followed by cellular apoptosis. We also found that STAT1/3 overexpression induced mitochondria respiratory complexes and ROS production. Additionally, ROS induced by H2O2 induced phosphorylation of STAT1/3 and promoted mitochondria importation. STAT1/3 deletion suppressed H2O2-induced acute cellular OCR, increasing the ROS level and indicating that STAT1/3 is necessary for ROS-induced mitochondria OCR and further ROS production, suggesting the existence of a STAT-ROS cycle. We next found that IFN induced mitochondria respiratory complexes followed by induction of OCR, ROS, and apoptosis, which were partially blocked by STAT1/3 deletion. Additionally, the suppression of ROS inhibited IFN‑induced STAT1/3 activation. Finally, we discovered that this cycle exists also in A431 and HeLa cancer cells. These results indicate that a STAT-ROS cycle extends IFN‑induced cellular apoptosis.

View Figures

View References

1	Arbuthnot P, Capovilla A and Kew M: Putative role of hepatitis B virus X protein in hepatocarcinogenesis: Effects on apoptosis, DNA repair, mitogen-activated protein kinase and JAK/STAT pathways. J Gastroenterol Hepatol. 15:357–368. 2000. View Article : Google Scholar : PubMed/NCBI
2	Beebe K, Lee WC and Micchelli CA: JAK/STAT signaling coordinates stem cell proliferation and multilineage differentiation in the Drosophila intestinal stem cell lineage. Dev Biol. 338:28–37. 2010. View Article : Google Scholar
3	Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE and McCubrey JA: JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 18:189–218. 2004. View Article : Google Scholar : PubMed/NCBI
4	Aaronson DS and Horvath CM: A road map for those who don't know JAK-STAT. Science. 296:1653–1655. 2002. View Article : Google Scholar : PubMed/NCBI
5	Schindler C and Darnell JE Jr: Transcriptional responses to polypeptide ligands: The JAK-STAT pathway. Annu Rev Biochem. 64:621–651. 1995. View Article : Google Scholar : PubMed/NCBI
6	Yuan ZL, Guan YJ, Chatterjee D and Chin YE: Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science. 307:269–273. 2005. View Article : Google Scholar : PubMed/NCBI
7	Xie Y, Kole S, Precht P, Pazin MJ and Bernier M: S-glutathionylation impairs signal transducer and activator of transcription 3 activation and signaling. Endocrinology. 150:1122–1131. 2009. View Article : Google Scholar :
8	Ray S, Boldogh I and Brasier AR: STAT3 NH2-terminal acetylation is activated by the hepatic acute-phase response and required for IL-6 induction of angiotensinogen. Gastroenterology. 129:1616–1632. 2005. View Article : Google Scholar : PubMed/NCBI
9	Horvath CM: The Jak-STAT pathway stimulated by interleukin 6. Sci STKE. 2004:tr92004.PubMed/NCBI
10	Leonard WJ: Role of Jak kinases and STATs in cytokine signal transduction. Int J Hematol. 73:271–277. 2001. View Article : Google Scholar : PubMed/NCBI
11	Levy JB, Schindler C, Raz R, Levy DE, Baron R and Horowitz MC: Activation of the JAK-STAT signal transduction pathway by oncostatin-M cultured human and mouse osteoblastic cells. Endocrinology. 137:1159–1165. 1996. View Article : Google Scholar : PubMed/NCBI
12	Lufei C, Ma J, Huang G, Zhang T, Novotny-Diermayr V, Ong CT and Cao X: GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional interaction. EMBO J. 22:1325–1335. 2003. View Article : Google Scholar : PubMed/NCBI
13	Tamminen P, Anugula C, Mohammed F, Anjaneyulu M, Larner AC and Sepuri NB: The import of the transcription factor STAT3 into mitochondria depends on GRIM-19, a component of the electron transport chain. J Biol Chem. 288:4723–4732. 2013. View Article : Google Scholar
14	Lee HJ, Oh YK, Rhee M, Lim JY, Hwang JY, Park YS, Kwon Y, Choi KH, Jo I, Park SI, et al: The role of STAT1/IRF-1 on synergistic ROS production and loss of mitochondrial transmembrane potential during hepatic cell death induced by LPS/d-GalN. J Mol Biol. 369:967–984. 2007. View Article : Google Scholar : PubMed/NCBI
15	Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A, et al: Function of mitochondrial Stat3 in cellular respiration. Science. 323:793–797. 2009. View Article : Google Scholar : PubMed/NCBI
16	Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL and Lesnefsky EJ: Production of reactive oxygen species by mitochondria: Central role of complex III. J Biol Chem. 278:36027–36031. 2003. View Article : Google Scholar : PubMed/NCBI
17	Batandier C, Guigas B, Detaille D, El-Mir MY, Fontaine E, Rigoulet M and Leverve XM: The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin. J Bioenerg Biomembr. 38:33–42. 2006. View Article : Google Scholar : PubMed/NCBI
18	Kim HS, Cho IH, Kim JE, Shin YJ, Jeon JH, Kim Y, Yang YM, Lee KH, Lee JW, Lee WJ, et al: Ethyl pyruvate has an anti-inflammatory effect by inhibiting ROS-dependent STAT signaling in activated microglia. Free Radic Biol Med. 45:950–963. 2008. View Article : Google Scholar : PubMed/NCBI
19	Liu T, Castro S, Brasier AR, Jamaluddin M, Garofalo RP and Casola A: Reactive oxygen species mediate virus-induced STAT activation: Role of tyrosine phosphatases. J Biol Chem. 279:2461–2469. 2004. View Article : Google Scholar
20	Simon AR, Rai U, Fanburg BL and Cochran BH: Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiol. 275:C1640–C1652. 1998. View Article : Google Scholar : PubMed/NCBI
21	Parkin J and Cohen B: An overview of the immune system. Lancet. 357:1777–1789. 2001. View Article : Google Scholar : PubMed/NCBI
22	Kiladjian JJ, Giraudier S and Cassinat B: Interferon-alpha for the therapy of myeloproliferative neoplasms: Targeting the malignant clone. Leukemia. 30:776–781. 2016. View Article : Google Scholar
23	Cao ZH, Zheng QY, Li GQ, Hu XB, Feng SL, Xu GL and Zhang KQ: STAT1-mediated down-regulation of Bcl-2 expression is involved in IFN-γ/TNF-α-induced apoptosis in NIT-1 cells. PLoS One. 10:e01209212015. View Article : Google Scholar
24	Ethiraj P, Veerappan K, Samuel S and Sivapatham S: Inhibitory effects of interferon-β on hepatocellular carcinoma HepG2 via Akt/STAT phosphorylation. Fundam Clin Pharmacol. 29:278–285. 2015. View Article : Google Scholar : PubMed/NCBI
25	Bello C, Vazquez-Blomquist D, Miranda J, Garcia Y, Novoa LI, Palenzuela D and Bello I: Regulation by IFN-α/IFN-γ co-formulation (HerberPAG^®) of genes involved in interferon-STAT-pathways and apoptosis in U87MG. Curr Top Med Chem. 14:351–358. 2014. View Article : Google Scholar
26	Zídek Z, Jansa P and Kmoníčková E: Activation of respiratory complex II by interferon-gamma and its inhibition by pyrimidine derivatives. Neuro Endocrinol Lett. 35(Suppl 2): 141–148. 2014.
27	Huang G, Chen Y, Lu H and Cao X: Coupling mitochondrial respiratory chain to cell death: An essential role of mitochondrial complex I in the interferon-beta and retinoic acid-induced cancer cell death. Cell Death Differ. 14:327–337. 2007. View Article : Google Scholar
28	Kim KB, Eton O, East MJ, Hodges C, Papadopoulos NE, Grimm EA and Bedikian AY: Pilot study of high-dose, concurrent biochemotherapy for advanced melanoma. Cancer. 101:596–603. 2004. View Article : Google Scholar : PubMed/NCBI
29	Henry SC, Schmidt EA, Fessler MB and Taylor GA: Palmitoylation of the immunity related GTPase, Irgm1: Impact on membrane localization and ability to promote mitochondrial fission. PLoS One. 9:e950212014. View Article : Google Scholar : PubMed/NCBI
30	Yang JY, Deng W, Chen Y, Fan W, Baldwin KM, Jope RS, Wallace DC and Wang PH: Impaired translocation and activation of mitochondrial Akt1 mitigated mitochondrial oxidative phosphorylation Complex V activity in diabetic myocardium. J Mol Cell Cardiol. 59:167–175. 2013. View Article : Google Scholar : PubMed/NCBI
31	Tian Z, Miyata K, Kadomatsu T, Horiguchi H, Fukushima H, Tohyama S, Ujihara Y, Okumura T, Yamaguchi S, Zhao J, et al: ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism. Nat Commun. 7:130162016. View Article : Google Scholar : PubMed/NCBI
32	Sansbury BE, Riggs DW, Brainard RE, Salabei JK, Jones SP and Hill BG: Responses of hypertrophied myocytes to reactive species: Implications for glycolysis and electrophile metabolism. Biochem J. 435:519–528. 2011. View Article : Google Scholar : PubMed/NCBI
33	Zorov DB, Juhaszova M and Sollott SJ: Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 94:909–950. 2014. View Article : Google Scholar : PubMed/NCBI
34	Chin YE, Kitagawa M, Kuida K, Flavell RA and Fu XY: Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol Cell Biol. 17:5328–5337. 1997. View Article : Google Scholar : PubMed/NCBI
35	Smith CC, Dixon RA, Wynne AM, Theodorou L, Ong SG, Subrayan S, Davidson SM, Hausenloy DJ and Yellon DM: Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore. Am J Physiol Heart Circ Physiol. 299:H1265–H1270. 2010. View Article : Google Scholar : PubMed/NCBI
36	Lemoine S, Zhu L, Legallois D, Massetti M, Manrique A and Hanouz JL: Atorvastatin-induced cardioprotection of human myocardium is mediated by the inhibition of mitochondrial permeability transition pore opening via tumor necrosis factor-α and Janus kinase/signal transducers and activators of transcription pathway. Anesthesiology. 118:1373–1384. 2013. View Article : Google Scholar : PubMed/NCBI
37	Dvorak K and Dvorak B: Role of interleukin-6 in Barrett's esophagus pathogenesis. World J Gastroenterol. 19:2307–2312. 2013. View Article : Google Scholar : PubMed/NCBI
38	Santambrogio P, Erba BG, Campanella A, Cozzi A, Causarano V, Cremonesi L, Gallì A, Della Porta MG, Invernizzi R and Levi S: Over-expression of mitochondrial ferritin affects the JAK2/STAT5 pathway in K562 cells and causes mitochondrial iron accumulation. Haematologica. 96:1424–1432. 2011. View Article : Google Scholar : PubMed/NCBI
39	Park SJ1, Lee JH, Kim HY, Choi YH, Park JS, Suh YH, Park SM, Joe EH and Jou I: Astrocytes, but not microglia, rapidly sense H₂O₂ via STAT6 phosphorylation, resulting in cyclooxygenase-2 expression and prostaglandin release. J Immunol. 188:5132–5141. 2012. View Article : Google Scholar : PubMed/NCBI
40	Jesel M, Isch-Treussard C, Poenaru S and Isch F: Electromyography in the study of thyrotoxic myopathies. Rev Electroencephalogr Neurophysiol Clin. 3:183–192. 1973.In French. View Article : Google Scholar : PubMed/NCBI
41	Sartor CI, Dziubinski ML, Yu CL, Jove R and Ethier SP: Role of epidermal growth factor receptor and STAT-3 activation in autonomous proliferation of SUM-102PT human breast cancer cells. Cancer Res. 57:978–987. 1997.PubMed/NCBI
42	Sahu RP and Srivastava SK: The role of STAT-3 in the induction of apoptosis in pancreatic cancer cells by benzyl isothiocyanate. J Natl Cancer Inst. 101:176–193. 2009. View Article : Google Scholar : PubMed/NCBI
43	Thoennissen NH, Iwanski GB, Doan NB, Okamoto R, Lin P, Abbassi S, Song JH, Yin D, Toh M, Xie WD, et al: Cucurbitacin B induces apoptosis by inhibition of the JAK/STAT pathway and potentiates antiproliferative effects of gemcitabine on pancreatic cancer cells. Cancer Res. 69:5876–5884. 2009. View Article : Google Scholar : PubMed/NCBI
44	Liby K, Voong N, Williams CR, Risingsong R, Royce DB, Honda T, Gribble GW, Sporn MB and Letterio JJ: The synthetic triterpenoid CDDO-Imidazolide suppresses STAT phosphorylation and induces apoptosis in myeloma and lung cancer cells. Clin Cancer Res. 12:4288–4293. 2006. View Article : Google Scholar : PubMed/NCBI
45	Mora LB, Buettner R, Seigne J, Diaz J, Ahmad N, Garcia R, Bowman T, Falcone R, Fairclough R, Cantor A, et al: Constitutive activation of Stat3 in human prostate tumors and cell lines: Direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res. 62:6659–6666. 2002.PubMed/NCBI
46	Ni Z, Lou W, Leman ES and Gao AC: Inhibition of constitutively activated Stat3 signaling pathway suppresses growth of prostate cancer cells. Cancer Res. 60:1225–1228. 2000.PubMed/NCBI
47	Burke WM, Jin X, Lin HJ, Huang M, Liu R, Reynolds RK and Lin J: Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells. Oncogene. 20:7925–7934. 2001. View Article : Google Scholar : PubMed/NCBI
48	Bromberg J: Stat proteins and oncogenesis. J Clin Invest. 109:1139–1142. 2002. View Article : Google Scholar : PubMed/NCBI