STAT3 activity regulates sensitivity to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cervical cancer cells

Nakamura,Hiroe; Taguchi,Ayumi; Kawana,Kei; Kawata,Akira; Yoshida,Mitsuyo; Fujimoto,Asaha; Ogishima,Juri; Sato,Masakazu; Inoue,Tomoko; Nishida,Haruka; Furuya,Hitomi; Tomio,Kensuke; Eguchi,Satoko; Mori-Uchino,Mayuyo; Yamashita,Aki; Adachi,Katsuyuki; Arimoto,Takahide; Wada-Hiraike,Osamu; Oda,Katsutoshi; Nagamatsu,Takeshi; Osuga,Yutaka; Fujii,Tomoyuki

doi:10.3892/ijo.2016.3681

STAT3 activity regulates sensitivity to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cervical cancer cells

Authors:
- Hiroe Nakamura
- Ayumi Taguchi
- Kei Kawana
- Akira Kawata
- Mitsuyo Yoshida
- Asaha Fujimoto
- Juri Ogishima
- Masakazu Sato
- Tomoko Inoue
- Haruka Nishida
- Hitomi Furuya
- Kensuke Tomio
- Satoko Eguchi
- Mayuyo Mori-Uchino
- Aki Yamashita
- Katsuyuki Adachi
- Takahide Arimoto
- Osamu Wada-Hiraike
- Katsutoshi Oda
- Takeshi Nagamatsu
- Yutaka Osuga
- Tomoyuki Fujii
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
Published online on: September 6, 2016 https://doi.org/10.3892/ijo.2016.3681
Pages: 2155-2162

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 cervical cancer, p53-induced apoptosis is abrogated by human papilloma virus (HPV)-derived oncoprotein E6. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) provides tumor-specific apoptosis in various cancers, including cervical cancer, the sensitivity differs depending on the cell lines. Signal transducer and activator of transcription 3 (STAT3) is a hub molecule that shifts the cellular fate to apoptosis or survival in response to cellular stresses. However, the contribution of STAT3 activity to TRAIL-induced apoptosis in cervical cancer remains unknown. We examined the TRAIL sensitivity in cervical cancer cells, using TRAIL-resistant (SiHa) and -sensitive (CaSki) cervical cancer cell lines and focused on STAT3 function involving the apoptotic pathway. STAT3 was inactivated by TRAIL stimulation in the CaSki cell line, but not in the SiHa cell line. We then inhibited STAT3 expression in the SiHa cell line using siRNA against STAT3 and suppressed STAT3 activity using a STAT3 inhibitor; both these treatments sensitized TRAIL-induced apoptosis in the SiHa cell line. Furthermore, the SiHa cells were exposed to tunicamycin (TM), an endoplasmic reticulum (ER) stress inducer that inactivates STAT3, with or without TRAIL. Accompanied by STAT3 inactivation, TM pretreatment significantly enhanced TRAIL-induced apoptosis. We therefore concluded that TRAIL-induced apoptosis was regulated by STAT3 in response to TRAIL stimulation. Our results also suggest that STAT3 inhibition increases the sensitivity of malignancies, particularly HPV-related cancer, to TRAIL-based therapy.

View Figures

View References

1	Ferlay JSI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Incidence/mortality data. GLOBOCAN 2012 1.0. 2012, https://www.iarc.fr.
2	Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A and Ashkenazi A: Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 271:12687–12690. 1996. View Article : Google Scholar : PubMed/NCBI
3	Zhang L and Fang B: Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther. 12:228–237. 2005. View Article : Google Scholar
4	Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA, et al: Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 3:673–682. 1995. View Article : Google Scholar : PubMed/NCBI
5	Kruyt FA: TRAIL and cancer therapy. Cancer Lett. 263:14–25. 2008. View Article : Google Scholar : PubMed/NCBI
6	Moody CA and Laimins LA: Human papillomavirus oncoproteins: Pathways to transformation. Nat Rev Cancer. 10:550–560. 2010. View Article : Google Scholar : PubMed/NCBI
7	Hougardy BM, Maduro JH, van der Zee AG, de Groot DJ, van den Heuvel FA, de Vries EG and de Jong S: Proteasome inhibitor MG132 sensitizes HPV-positive human cervical cancer cells to rhTRAIL-induced apoptosis. Int J Cancer. 118:1892–1900. 2006. View Article : Google Scholar
8	Yu H, Lee H, Herrmann A, Buettner R and Jove R: Revisiting STAT3 signalling in cancer: New and unexpected biological functions. Nat Rev Cancer. 14:736–746. 2014. View Article : Google Scholar : PubMed/NCBI
9	Akira S: Roles of STAT3 defined by tissue-specific gene targeting. Oncogene. 19:2607–2611. 2000. View Article : Google Scholar : PubMed/NCBI
10	Levy DE and Lee CK: What does Stat3 do? J Clin Invest. 109:1143–1148. 2002. View Article : Google Scholar : PubMed/NCBI
11	Dudley AC, Thomas D, Best J and Jenkins A: The STATs in cell stress-type responses. Cell Commun Signal. 2:82004. View Article : Google Scholar : PubMed/NCBI
12	Wada T and Penninger JM: Mitogen-activated protein kinases in apoptosis regulation. Oncogene. 23:2838–2849. 2004. View Article : Google Scholar : PubMed/NCBI
13	Ramírez de Arellano A, Lopez-Pulido EI, Martínez-Neri PA, Estrada Chávez C, González Lucano R, Fafutis-Morris M, Aguilar-Lemarroy A, Muñoz-Valle JF and Pereira-Suárez AL: STAT3 activation is required for the antiapoptotic effects of prolactin in cervical cancer cells. Cancer Cell Int. 15:832015. View Article : Google Scholar : PubMed/NCBI
14	Banerjee K and Resat H: Constitutive activation of STAT3 in breast cancer cells: A review. Int J Cancer. 138:2570–2578. 2016. View Article : Google Scholar
15	Benekli M, Xia Z, Donohue KA, Ford LA, Pixley LA, Baer MR, Baumann H and Wetzler M: Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival. Blood. 99:252–257. 2002. View Article : Google Scholar : PubMed/NCBI
16	Takemoto S, Ushijima K, Kawano K, Yamaguchi T, Terada A, Fujiyoshi N, Nishio S, Tsuda N, Ijichi M, Kakuma T, et al: Expression of activated signal transducer and activator of transcription-3 predicts poor prognosis in cervical squamous-cell carcinoma. Br J Cancer. 101:967–972. 2009. View Article : Google Scholar : PubMed/NCBI
17	Schoppmann SF, Jesch B, Friedrich J, Jomrich G, Maroske F and Birner P: Phosphorylation of signal transducer and activator of transcription 3 (STAT3) correlates with Her-2 status, carbonic anhydrase 9 expression and prognosis in esophageal cancer. Clin Exp Metastasis. 29:615–624. 2012. View Article : Google Scholar : PubMed/NCBI
18	Mali SB: Review of STAT3 (Signal Transducers and Activators of Transcription) in head and neck cancer. Oral Oncol. 51:565–569. 2015. View Article : Google Scholar : PubMed/NCBI
19	Kusaba M, Nakao K, Goto T, Nishimura D, Kawashimo H, Shibata H, Motoyoshi Y, Taura N, Ichikawa T, Hamasaki K, et al: Abrogation of constitutive STAT3 activity sensitizes human hepatoma cells to TRAIL-mediated apoptosis. J Hepatol. 47:546–555. 2007. View Article : Google Scholar : PubMed/NCBI
20	Lanuti P, Bertagnolo V, Pierdomenico L, Bascelli A, Santavenere E, Alinari L, Capitani S, Miscia S and Marchisio M: Enhancement of TRAIL cytotoxicity by AG-490 in human ALL cells is characterized by downregulation of cIAP-1 and cIAP-2 through inhibition of Jak2/Stat3. Cell Res. 19:1079–1089. 2009. View Article : Google Scholar : PubMed/NCBI
21	Singh TR, Shankar S and Srivastava RK: HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma. Oncogene. 24:4609–4623. 2005. View Article : Google Scholar : PubMed/NCBI
22	Fulda S: Histone deacetylase (HDAC) inhibitors and regulation of TRAIL-induced apoptosis. Exp Cell Res. 318:1208–1212. 2012. View Article : Google Scholar : PubMed/NCBI
23	Earel JK Jr, VanOosten RL and Griffith TS: Histone deacetylase inhibitors modulate the sensitivity of tumor necrosis factor-related apoptosis-inducing ligand-resistant bladder tumor cells. Cancer Res. 66:499–507. 2006. View Article : Google Scholar : PubMed/NCBI
24	Fandy TE, Shankar S, Ross DD, Sausville E and Srivastava RK: Interactive effects of HDAC inhibitors and TRAIL on apoptosis are associated with changes in mitochondrial functions and expressions of cell cycle regulatory genes in multiple myeloma. Neoplasia. 7:646–657. 2005. View Article : Google Scholar : PubMed/NCBI
25	Gupta M, Han JJ, Stenson M, Wellik L and Witzig TE: Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: Implications for therapy. Leukemia. 26:1356–1364. 2012. View Article : Google Scholar
26	Ganapathy S, Chen Q, Singh KP, Shankar S and Srivastava RK: Resveratrol enhances antitumor activity of TRAIL in prostate cancer xenografts through activation of FOXO transcription factor. PLoS One. 5:e156272010. View Article : Google Scholar
27	Taguchi A, Koga K, Kawana K, Makabe T, Sue F, Miyashita M, Yoshida M, Urata Y, Izumi G, Tkamura M, et al: Resveratrol enhances apoptosis in endometriotic stromal cells. Am J Reprod Immunol. 75:486–492. 2016. View Article : Google Scholar : PubMed/NCBI
28	Quoc Trung L, Espinoza JL, Takami A and Nakao S: Resveratrol induces cell cycle arrest and apoptosis in malignant NK cells via JAK2/STAT3 pathway inhibition. PLoS One. 8:e551832013. View Article : Google Scholar : PubMed/NCBI
29	Kotha A, Sekharam M, Cilenti L, Siddiquee K, Khaled A, Zervos AS, Carter B, Turkson J and Jove R: Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein. Mol Cancer Ther. 5:621–629. 2006. View Article : Google Scholar : PubMed/NCBI
30	Tameda M, Sugimoto K, Shiraki K, Inagaki Y, Ogura S, Kasai C, Yoneda M, Okamoto R, Yamamoto N, Takei Y, et al: Resveratrol sensitizes HepG2 cells to TRAIL-induced apoptosis. Anticancer Drugs. 25:1028–1034. 2014. View Article : Google Scholar : PubMed/NCBI
31	Bharti AC, Donato N and Aggarwal BB: Curcumin (diferu-loylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. J Immunol. 171:3863–3871. 2003. View Article : Google Scholar : PubMed/NCBI
32	Alexandrow MG, Song LJ, Altiok S, Gray J, Haura EB and Kumar NB: Curcumin: A novel Stat3 pathway inhibitor for chemoprevention of lung cancer. Eur J Cancer Prev. 21:407–412. 2012. View Article : Google Scholar :
33	Shankar S, Chen Q, Sarva K, Siddiqui I and Srivastava RK: Curcumin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells: Molecular mechanisms of apoptosis, migration and angiogenesis. J Mol Signal. 2:102007. View Article : Google Scholar : PubMed/NCBI
34	Park S, Cho DH, Andera L, Suh N and Kim I: Curcumin enhances TRAIL-induced apoptosis of breast cancer cells by regulating apoptosis-related proteins. Mol Cell Biochem. 383:39–48. 2013. View Article : Google Scholar : PubMed/NCBI
35	Glienke W, Maute L, Wicht J and Bergmann L: Curcumin inhibits constitutive STAT3 phosphorylation in human pancreatic cancer cell lines and downregulation of survivin/BIRC5 gene expression. Cancer Invest. 28:166–171. 2010. View Article : Google Scholar : PubMed/NCBI
36	Yu H, Kortylewski M and Pardoll D: Crosstalk between cancer and immune cells: Role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 7:41–51. 2007. View Article : Google Scholar
37	Zhang HF and Lai R: STAT3 in Cancer - Friend or Foe? Cancers (Basel). 6:1408–1440. 2014. View Article : Google Scholar
38	Pensa S, Regis G, Boselli D, Novelli F and Poli V: STAT1 and STAT3 in tumorigenesis: Two sides of the same coin. Madame Curie Bioscience Database. Landes Bioscience; Austin, TX: 2009
39	Pectasides D, Kamposioras K, Papaxoinis G and Pectasides E: Chemotherapy for recurrent cervical cancer. Cancer Treat Rev. 34:603–613. 2008. View Article : Google Scholar : PubMed/NCBI
40	Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR, Yip ML, Jove R, McLaughlin MM, Lawrence NJ, et al: Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci USA. 104:7391–7396. 2007. View Article : Google Scholar : PubMed/NCBI
41	Kimura K, Yamada T, Matsumoto M, Kido Y, Hosooka T, Asahara S, Matsuda T, Ota T, Watanabe H, Sai Y, et al: Endoplasmic reticulum stress inhibits STAT3-dependent suppression of hepatic gluconeogenesis via dephosphorylation and deacetylation. Diabetes. 61:61–73. 2012. View Article : Google Scholar :
42	Yang Z, Liu Y, Liao J, Gong C, Sun C, Zhou X, Wei X, Zhang T, Gao Q, Ma D, et al: Quercetin induces endoplasmic reticulum stress to enhance cDDP cytotoxicity in ovarian cancer: Involvement of STAT3 signaling. FEBS J. 282:1111–1125. 2015. View Article : Google Scholar : PubMed/NCBI
43	Oyadomari S and Mori M: Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 11:381–389. 2004. View Article : Google Scholar
44	Shukla S, Mahata S, Shishodia G, Pandey A, Tyagi A, Vishnoi K, Basir SF, Das BC and Bharti AC: Functional regulatory role of STAT3 in HPV16-mediated cervical carcinogenesis. PLoS One. 8:e678492013. View Article : Google Scholar : PubMed/NCBI
45	Hetz C: The unfolded protein response: Controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 13:89–102. 2012.PubMed/NCBI
46	Jiang CC, Chen LH, Gillespie S, Kiejda KA, Mhaidat N, Wang YF, Thorne R, Zhang XD and Hersey P: Tunicamycin sensitizes human melanoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by up-regulation of TRAIL-R2 via the unfolded protein response. Cancer Res. 67:5880–5888. 2007. View Article : Google Scholar : PubMed/NCBI
47	Jung YH, Lim EJ, Heo J, Kwon TK and Kim YH: Tunicamycin sensitizes human prostate cells to TRAIL-induced apoptosis by upregulation of TRAIL receptors and downregulation of cIAP2. Int J Oncol. 40:1941–1948. 2012.PubMed/NCBI
48	Hasegawa A, Osuga Y, Hirota Y, Hamasaki K, Kodama A, Harada M, Tajima T, Takemura Y, Hirata T, Yoshino O, et al: Tunicamycin enhances the apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand in endometriotic stromal cells. Hum Reprod. 24:408–414. 2009. View Article : Google Scholar
49	Shiraishi T, Yoshida T, Nakata S, Horinaka M, Wakada M, Mizutani Y, Miki T and Sakai T: Tunicamycin enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human prostate cancer cells. Cancer Res. 65:6364–6370. 2005. View Article : Google Scholar : PubMed/NCBI
50	Hu Y, Hong Y, Xu Y, Liu P, Guo DH and Chen Y: Inhibition of the JAK/STAT pathway with ruxolitinib overcomes cisplatin resistance in non-small-cell lung cancer NSCLC. Apoptosis. 19:1627–1636. 2014. View Article : Google Scholar : PubMed/NCBI
51	Selvendiran K, Bratasz A, Kuppusamy ML, Tazi MF, Rivera BK and Kuppusamy P: Hypoxia induces chemoresistance in ovarian cancer cells by activation of signal transducer and activator of transcription 3. Int J Cancer. 125:2198–2204. 2009. View Article : Google Scholar : PubMed/NCBI
52	Dasari S and Tchounwou PB: Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol. 740:364–378. 2014. View Article : Google Scholar : PubMed/NCBI