MUC5AC protects pancreatic cancer cells from TRAIL-induced death pathways

Hoshi,Hirotaka; Sawada,Tetsuji; Uchida,Motoyuki; Iijima,Hiroko; Kimura,Kenjiro; Hirakawa,Kosei; Wanibuchi,Hideki

doi:10.3892/ijo.2013.1760

MUC5AC protects pancreatic cancer cells from TRAIL-induced death pathways

Authors:
- Hirotaka Hoshi
- Tetsuji Sawada
- Motoyuki Uchida
- Hiroko Iijima
- Kenjiro Kimura
- Kosei Hirakawa
- Hideki Wanibuchi
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Affiliations: Biomedical Research Laboratories, Kureha Corporation, Shinjuku-ku, Tokyo 169-8503, Japan, Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan, Department of Pathology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
Published online on: January 3, 2013 https://doi.org/10.3892/ijo.2013.1760
Pages: 887-893

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Abstract

We have previously reported that a specific siRNA transfected MUC5AC could knockdown MUC5AC expression and suppress in vivo tumor growth and metastasis, although it had no effects on in vitro cell growth, cell survival, proliferation and morphology. In the present study, we investigated which host immune cells induced these effects and how the effects were induced using immunocyte-depleted animal models. The tumor growth of SW1990/si-MUC5AC cells, which show no tumor growth when implanted subcutaneously into a nude mouse, was recovered when neutrophils were removed by anti-Gr-1 mAb administration. This result suggests that MUC5AC may suppress the antitumor effects of neutrophils by allowing tumor cells to escape the host immune system. Subsequently, we investigated the effects of MUC5AC on apoptosis induction mediated by TNF-related apoptosis-inducing ligand (TRAIL), one of the antitumor mechanisms of neutrophils. SW1990/si-MUC5AC cells showed significantly increased active caspase 3 expression after the addition of TRAIL. On the other hand, SW1990/si-mock cells showed no such changes. Our results indicate that MUC5AC inhibits TRAIL‑induced apoptosis in human pancreatic cancer and may serve as an important indicator in diagnosis and prognosis.

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1	Wang Z, Song W, Aboukameel A, Mohammad M, Wang G, Banerjee S, Kong D, Wang S, Sarkar FH and Mohammad RM: TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and invasion in pancreatic cancer. Int J Cancer. 123:958–966. 2008. View Article : Google Scholar : PubMed/NCBI
2	Sheehan JK, Brazeau C, Kutay S, Pigeon H, Kirkham S, Howard M and Thornton DJ: Physical characterization of the MUC5AC mucin: a highly oligomeric glycoprotein whether isolated from cell culture or in vivo from respiratory mucous secretions. Biochem J. 347:37–44. 2000. View Article : Google Scholar
3	Hollingsworth MA and Swanson BJ: Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 4:45–60. 2004. View Article : Google Scholar : PubMed/NCBI
4	Ho JJL, Crawley S, Pan PL, Farrelly ER and Kim YS: Secretion of MUC5AC mucin from pancreatic cancer cells in response to forskolin and VIP. Biochem Biophys Res Commun. 294:680–686. 2002. View Article : Google Scholar : PubMed/NCBI
5	Tecchio C, Huber V, Scapini P, Calzetti F, Margotto D, Todeschini G, Pilla L, Martinelli G, Pizzolo G, Rivoltini L and Cassatella MA: IFNalpha-stimulated neutrophils and monocytes release a soluble form of TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) displaying apoptotic activity on leukemic cells. Blood. 103:3837–3844. 2004. View Article : Google Scholar
6	Stockmeyer B, Beyer T, Neuhuber W, Repp R, Kalden JR, Valerius T and Herrmann M: Polymorphonuclear granulocytes induce antibody-dependent apoptosis in human breast cancer cells. J Immunol. 171:5124–5129. 2003. View Article : Google Scholar : PubMed/NCBI
7	Challacombe JM, Suhrbier A, Parsons PG, Jones B, Hampson P, Kavanagh D, Rainger GE, Morris M, Lord JM, Le TT, Hoang-Le D and Ogbourne SM: Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. J Immunol. 177:8123–8132. 2006. View Article : Google Scholar : PubMed/NCBI
8	Koga Y, Matsuzaki A, Suminoe A, Hattori H and Hara T: Neutrophil-derived TNF-related apoptosis-inducing ligand (TRAIL): a novel mechanism of antitumor effect by neutrophils. Cancer Res. 64:1037–1043. 2004. View Article : Google Scholar : PubMed/NCBI
9	Kemp TJ, Ludwig AT, Earel JK, Moore JM, Vanoosten RL, Moses B, Leidal K, Nauseef WM and Griffith TS: Neutrophil stimulation with Mycobacterium bovis bacillus Calmette-Guérin (BCG) results in the release of functional soluble TRAIL/Apo-2L. Blood. 106:3474–3482. 2005.
10	de Vries EG, Gietema JA and de Jong S: Tumor necrosis factor-related apoptosis-inducing ligand pathway and its therapeutic implications. Clin Cancer Res. 12:2390–2393. 2006.
11	Voortman J and Resende TP: TRAIL therapy in non-small cell lung cancer cells: sensitization to death receptor-mediated apoptosis by proteasome inhibitor bortezomib. Mol Cancer Ther. 6:2103–2112. 2007. View Article : Google Scholar
12	Hoshi H, Sawada T, Uchida M, Saito H, Iijima H, Toda-Agetsuma M, Wada T, Yamazoe S, Tanaka H, Kimura K, Kakehashi A, Wei M, Hirakawa K and Wanibuchi H: Tumor-associated MUC5AC stimulates in vivo tumorigenicity of human pancreatic cancer. Int J Oncol. 38:619–627. 2011.PubMed/NCBI
13	Hernandez-Ilizaliturri FJ, Jupudy V, Ostberg J, Oflazoglu E, Huberman A, Repasky E and Czuczman MS: Neutrophils contribute to the biological antitumor activity of rituximab in a non-Hodgkin’s lymphoma severe combined immunodeficiency mouse model. Clin Cancer Res. 9:5866–5873. 2003.PubMed/NCBI
14	Singh PK and Hollingsworth MA: Cell surface-associated mucins in signal transduction. Trends Cell Biol. 16:467–476. 2006. View Article : Google Scholar : PubMed/NCBI
15	Lane D, Côté M, Grondin R, Couture MC and Piché A: Acquired resistance to TRAIL-induced apoptosis in human ovarian cancer cells is conferred by increased turnover of mature caspase-3. Mol Cancer Ther. 5:509–521. 2006. View Article : Google Scholar : PubMed/NCBI
16	Lane D, Robert V, Grondin R, Rancourt C and Piché A: Malignant ascites protect against TRAIL-induced apoptosis by activating the PI3K/Akt pathway in human ovarian carcinoma cells. Int J Cancer. 121:1227–1237. 2007. View Article : Google Scholar
17	Di Carlo E, Forni G, Lollini P, Colombo MP, Modesti A and Musiani P: The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood. 97:339–345. 2001.PubMed/NCBI
18	Alvarez MJ, Prada F, Salvatierra E, Bravo AI, Lutzky VP, Carbone C, Pitossi FJ, Chuluyan HE and Podhajcer OL: Secreted protein acidic and rich in cysteine produced by human melanoma cells modulates polymorphonuclear leukocyte recruitment and antitumor cytotoxic capacity. Cancer Res. 65:5123–5132. 2005. View Article : Google Scholar
19	Chen YL, Chen SH, Wang JY and Yang BC: Fas ligand on tumor cells mediates inactivation of neutrophils. J Immunol. 171:1183–1191. 2003. View Article : Google Scholar : PubMed/NCBI
20	Sanford MA, Yan Y, Canfield SE, Hassan W, Selleck WA, Atkinson G, Chen SH and Hall SJ: Independent contributions of GR-1+ leukocytes and Fas/FasL interactions to induce apoptosis following interleukin-12 gene therapy in a metastatic model of prostate cancer. Hum Gene Ther. 12:1485–1498. 2001.PubMed/NCBI
21	Niitsu N, Khori M, Hayama M, Kajiwara K, Higashihara M and Tamaru J: Phase I/II study of the rituximab-EPOCT regimen in combination with granulocyte colony-stimulating factor in patients with relapsed or refractory follicular lymphoma including evaluation of its cardiotoxicity using B-type natriuretic peptide and troponin T levels. Clin Cancer Res. 11:697–702. 2005.
22	Otten MA, Rudolph E, Dechant M, Tuk CW, Reijmers RM, Beelen RH, van de Winkel JG and van Egmond M: Immature neutrophils mediate tumor cell killing via IgA but not IgG Fc receptors. J Immunol. 174:5472–5480. 2005. View Article : Google Scholar : PubMed/NCBI
23	Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA and Goodwin RG: 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
24	Schimmer AD: Inhibition of apoptosis proteins: translating basic knowledge into clinical practice. Cancer Res. 64:7183–7190. 2004. View Article : Google Scholar : PubMed/NCBI
25	Wei Y, Fan T and Yu M: Inhibitor of apoptosis proteins and apoptosis. Acta Biochim Biophys Sin (Shanghai). 40:278–288. 2009. View Article : Google Scholar
26	Komatsu M, Jepson S, Arango ME, Carraway CAC and Carraway KL: Muc4/sialomucin complex, an intramembrane modulator of ErbB2/HER2/Neu, potentiates primary tumor growth and suppresses apoptosis in a xenotransplanted tumor. Oncogene. 20:461–470. 2001. View Article : Google Scholar : PubMed/NCBI
27	Workman HC, Sweeney C and Carraway KL III: The membrane mucin Muc4 inhibits apoptosis induced by multiple insults via ErbB2-dependent and ErbB2-independent mechanisms. Cancer Res. 69:2845–2852. 2009. View Article : Google Scholar : PubMed/NCBI
28	Baratelli F, Krysan K, Heuzé-Vourc’h N, Zhu L, Escuadro B, Sharma S, Reckamp K, Dohadwala M and Dubinett SM: PGE2 confers survivin-dependent apoptosis resistance in human monocyte-derived dendritic cells. J Leukoc Biol. 78:555–564. 2005. View Article : Google Scholar : PubMed/NCBI
29	Leone V, di Palma A, Ricchi P, Acquaviva F, Giannouli M, Di Prisco AM, Iuliano F and Acquaviva AM: PGE2 inhibits apoptosis in human adenocarcinoma Caco-2 cell line through Ras-PI3K association and cAMP-dependent kinase A activation. Am J Physiol Gastrointest Liver Physiol. 293:G673–G681. 2007. View Article : Google Scholar : PubMed/NCBI