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01.02.2007 | Original Article

Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10

verfasst von: Mingzhong Zheng, Dora Bocangel, Blair Doneske, Abner Mhashilkar, Rajagopal Ramesh, Kelly K. Hunt, Suhendan Ekmekcioglu, R. Bryan Sutton, Nancy Poindexter, Elizabeth A. Grimm, Sunil Chada

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 2/2007

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Abstract

The melanoma differentiation-associated gene-7 (mda-7/IL-24) is a unique member of the interleukin 10 (IL-10) family of cytokines, with ubiquitous tumor cell pro-apoptotic activity. Recent data have shown that IL-24 is secreted as a glycosylated protein and functions as a pro-Th1 cytokine and as a potent anti-angiogenic molecule. In this study, we analyzed the activity of Ad-mda7 and its protein product, secreted IL-24, against human breast cancer cells. We show that Ad-mda7 transduction of human breast cancer cells results in G₂/M phase cell cycle arrest and apoptotic cell death, which correlates with secretion of IL-24 protein. Neutralizing antibody against IL-24 significantly inhibited Ad-mda7 cytotoxicity. IL-24 and IL-10 both engage their cognate receptors on breast cancer cells resulting in phosphorylation and activation of STAT3, however, IL-10 receptor binding failed to induce cell killing, indicating that tumor cell killing by IL-24 is independent of STAT3 phosphorylation. Treatment with exogenous IL-24 induced apoptosis in breast cancer cells and this effect was abolished by addition of anti-IL-24 antibody or anti-IL-20R1, indicating that bystander cell killing is mediated via IL-24 binding to the IL-20R1/IL-20R2 heterodimeric receptor complex. Co-administration of the related cytokine IL-10 inhibited killing mediated by IL-24 and concomitantly inhibited IL-24 mediated up-regulation of the tumor suppressor proteins, p53 and p27^Kip1. In summary, we have defined a tumor-selective cytotoxic bystander role for secreted IL-24 protein and identified a novel receptor-mediated death pathway in breast cancer cells, wherein the related cytokines IL-24 and IL-10 exhibit antagonistic activity.

Goldstein L, Cianfrocca M, von Mehren M, Gradel T, Kilpatrick D, Vaders L, Smolenski-Burke S, Brady D, Vogel L (2000) Breast cancer research. Fox Chase Cancer Center Scientific Report. In: Fox Chase Cancer Center, Philadelphia, pp 158–162

Russo J, Yang X, Hu YF, Bove BA, Huang Y, Silva ID, Tahin Q, Wu Y, Higgy N, Zekri A, Russo IH (1998) Biological and molecular basis of human breast cancer. Front Biosci 3:D944–D960PubMed

Parkin DM, Pisani P, Ferlay J (1993) Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 54:594–606PubMed

Blumberg H, Conklin D, Xu WF, Grossmann A, Brender T, Carollo S, Eagan M, Foster D, Haldeman BA, Hammond A et al (2001) Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104:9–19CrossRefPubMed

Huang EY, Madireddi MT, Gopalkrishnan RV, Leszczyniecka M, Su Z, Lebedeva IV, Kang D, Jiang H, Lin JJ, Alexandre D et al (2001) Genomic structure, chromosomal localization and expression profile of a novel melanoma differentiation associated (mda-7) gene with cancer specific growth suppressing and apoptosis inducing properties. Oncogene 20:7051–7063CrossRefPubMed

Caudell EG, Mumm JB, Poindexter N, Ekmekcioglu S, Mhashilkar AM, Yang XH, Retter MW, Hill P, Chada S, Grimm EA (2002) The protein product of the tumor suppressor gene, melanoma differentiation-associated gene 7, exhibits immunostimulatory activity and is designated IL-24. J Immunol 168:6041–6046PubMed

Jiang H, Su ZZ, Lin JJ, Goldstein NI, Young CS, Fisher PB (1996) The melanoma differentiation associated gene mda-7 suppresses cancer cell growth. Proc Natl Acad Sci USA 93:9160–9165CrossRefPubMed

Madireddi MT, Su ZZ, Young CS, Goldstein NI, Fisher PB (2000) Mda-7, a novel melanoma differentiation associated gene with promise for cancer gene therapy. Adv Exp Med Biol 465:239–261PubMedCrossRef

Mhashilkar AM, Schrock RD, Hindi M, Liao J, Sieger K, Kourouma F, Zou-Yang XH, Onishi E, Takh O, Vedvick TS et al (2001) Melanoma differentiation associated gene-7 (mda-7): a novel anti-tumor gene for cancer gene therapy. Mol Med 7:271–282PubMed

10.

Sarkar D, Su ZZ, Lebedeva IV, Sauane M, Gopalkrishnan RV, Valerie K, Dent P, Fisher PB (2002) mda-7 (IL-24) Mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK. Proc Natl Acad Sci USA 99:10054–10059CrossRefPubMed

11.

Chada S, Sutton RB, Ekmekcioglu S, Ellerhorst J, Mumm JB, Leitner WW, Yang HY, Sahin AA, Hunt KK, Fuson KL et al (2004) MDA-7/IL-24 is a unique cytokine–tumor suppressor in the IL-10 family. Int Immunopharmacol 4:649–667CrossRefPubMed

12.

Ramesh R, Mhashilkar AM, Tanaka F, Saito Y, Branch CD, Sieger K, Mumm JB, Stewart AL, Boquoi A, Dumoutier L et al (2003) Melanoma differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor. Cancer Res 63:5105–5113PubMed

13.

Ramesh R, Ito I, Gopalan B, Saito Y, Mhashilkar AM, Chada S (2004) Ectopic production of MDA-7/IL-24 inhibits invasion and migration of human lung cancer cells. Mol Ther 9:510–518CrossRefPubMed

14.

Saito Y, Miyahara R, Gopalan B, Litvak A, Inoue S, Shanker M, Branch CD, Mhashilkar AM, Roth JA, Chada S, Ramesh R (2005) Selective induction of cell cycle arrest and apoptosis in human prostate cancer cells through adenoviral transfer of the melanoma differentiation-associated-7 (mda-7)/interleukin-24 (IL-24) gene. Cancer Gene Ther 12:238–247CrossRefPubMed

15.

Saeki T, Mhashilkar A, Swanson X, Zou-Yang XH, Sieger K, Kawabe S, Branch CD, Zumstein L, Meyn RE, Roth JA et al (2002) Inhibition of human lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo. Oncogene 21:4558–4566CrossRefPubMed

16.

McKenzie T, Liu Y, Fanale M, Swisher SG, Chada S, Hunt KK (2004) Combination therapy of Ad-mda7 and trastuzumab increases cell death in Her-2/neu-overexpressing breast cancer cells. Surgery 136:437–442CrossRefPubMed

17.

Tong AW, Nemunaitis J, Su D, Zhang Y, Cunningham C, Senzer N, Netto G, Rich D, Mhashilkar A, Parker K et al (2005) Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients. Mol Ther 11:160–172CrossRefPubMed

18.

Cunningham CC, Chada S, Merritt JA, Tong A, Senzer N, Zhang Y, Mhashilkar A, Parker K, Vukelja S, Richards D et al (2005) Clinical and local biological effects of an intratumoral injection of mda-7 (IL24; INGN 241) in patients with advanced carcinoma: a phase I study. Mol Ther 11:149–159CrossRefPubMed

19.

Saeki T, Mhashilkar A, Chada S, Branch C, Roth JA, Ramesh R (2000) Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro. Gene Ther 7:2051–2057CrossRefPubMed

20.

Ekmekcioglu S, Ellerhorst J, Mhashilkar AM, Sahin AA, Read CM, Prieto VG, Chada S, Grimm EA (2001) Down-regulated melanoma differentiation associated gene (mda-7) expression in human melanomas. Int J Cancer 94:54–59CrossRefPubMed

21.

Su ZZ, Madireddi MT, Lin JJ, Young CS, Kitada S, Reed JC, Goldstein NI, Fisher PB (1998) The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice. Proc Natl Acad Sci USA 95:14400–14405CrossRefPubMed

22.

Pataer A, Vorburger SA, Barber GN, Chada S, Mhashilkar AM, Zou-Yang H, Stewart AL, Balachandran S, Roth JA, Hunt KK, Swisher SG (2002) Adenoviral transfer of the melanoma differentiation-associated gene 7 (mda7) induces apoptosis of lung cancer cells via up-regulation of the double-stranded RNA-dependent protein kinase (PKR). Cancer Res 62:2239–2243PubMed

23.

Lebedeva IV, Su ZZ, Sarkar D, Kitada S, Dent P, Waxman S, Reed JC, Fisher PB (2003) Melanoma differentiation associated gene-7, mda-7/interleukin-24, induces apoptosis in prostate cancer cells by promoting mitochondrial dysfunction and inducing reactive oxygen species. Cancer Res 63:8138–8144PubMed

24.

Nishikawa T, Ramesh R, Munshi A, Chada S, Meyn RE (2004) Adenovirus-mediated mda-7 (IL24) gene therapy suppresses angiogenesis and sensitizes NSCLC xenograft tumors to radiation. Mol Ther 9:818–828CrossRefPubMed

25.

Su ZZ, Lebedeva IV, Sarkar D, Gopalkrishnan RV, Sauane M, Sigmon C, Yacoub A, Valerie K, Dent P, Fisher PB (2003) Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces growth suppression, apoptosis and radiosensitization in malignant gliomas in a p53-independent manner. Oncogene 22:1164–1180CrossRefPubMed

26.

Pataer A, Chada S, Hunt KK, Roth JA, Swisher SG (2003) Adenoviral melanoma differentiation-associated gene 7 induces apoptosis in lung cancer cells through mitochondrial permeability transition-independent cytochrome c release. J Thorac Cardiovasc Surg 125:1328–1335CrossRefPubMed

27.

Kotenko SV, Krause CD, Izotova LS, Pollack BP, Wu W, Pestka S (1997) Identification and functional characterization of a second chain of the interleukin-10 receptor complex. EMBO J 16:5894–5903CrossRefPubMed

28.

Liu Y, Wei SH, Ho AS, de Waal Malefyt R, Moore KW (1994) Expression cloning and characterization of a human IL-10 receptor. J Immunol 152:1821–1829PubMed

29.

Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, Donnelly RP, Pestka S (2001) Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. J Biol Chem 276:2725–2732CrossRefPubMed

30.

Dumoutier L, Leemans C, Lejeune D, Kotenko SV, Renauld JC (2001) Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J Immunol 167:3545–3549PubMed

31.

Wang M, Tan Z, Zhang R, Kotenko SV, Liang P (2002) Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2. J Biol Chem 277:7341–7347CrossRefPubMed

32.

Parrish-Novak J, Xu W, Brender T, Yao L, Jones C, West J, Brandt C, Jelinek L, Madden K, McKernan PA et al (2002) Interleukins 19, 20, and 24 signal through two distinct receptor complexes. Differences in receptor-ligand interactions mediate unique biological functions. J Biol Chem 277:47517–47523CrossRefPubMed

33.

Lebedeva IV, Su ZZ, Chang Y, Kitada S, Reed JC, Fisher PB (2002) The cancer growth suppressing gene mda-7 induces apoptosis selectively in human melanoma cells. Oncogene 21:708–718CrossRefPubMed

34.

Lebedeva IV, Sarkar D, Su ZZ, Kitada S, Dent P, Stein CA, Reed JC, Fisher PB (2003) Bcl-2 and Bcl-x(L) differentially protect human prostate cancer cells from induction of apoptosis by melanoma differentiation associated gene-7, mda-7/IL-24. Oncogene 22:8758–8773CrossRefPubMed

35.

Sarkar D, Su ZZ, Lebedeva IV, Sauane M, Gopalkrishnan RV, Dent P, Fisher PB (2002) mda-7 (IL-24): signaling and functional roles. Biotechniques (Suppl):30–39

36.

Sauane M, Gopalkrishnan RV, Lebedeva I, Mei MX, Sarkar D, Su ZZ, Kang DC, Dent P, Pestka S, Fisher PB (2003) Mda-7/IL-24 induces apoptosis of diverse cancer cell lines through JAK/STAT-independent pathways. J Cell Physiol 196:334–345CrossRefPubMed

37.

Nicholson KM, Anderson NG (2002) The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14:381–395CrossRefPubMed

38.

Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, Cristiano BE, Pearson RB, Phillips WA (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64:7678–7681CrossRefPubMed

39.

Simstein R, Burow M, Parker A, Weldon C, Beckman B (2003) Apoptosis, chemoresistance, and breast cancer: insights from the MCF-7 cell model system. Exp Biol Med (Maywood) 228:995–1003

40.

Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB (2004) Interleukin-10 and related cytokines and receptors. Annu Rev Immunol 22:929–979CrossRefPubMed

41.

Gopalkrishnan RV, Sauane M, Fisher PB (2004) Cytokine and tumor cell apoptosis inducing activity of mda-7/IL-24. Int Immunopharmacol 4:635–647CrossRefPubMed

42.

Chada S, Bocangel D, Ramesh R, Grimm EA, Mumm JB, Mhashilkar AM, Zheng M (2005) mda-7/IL24 kills pancreatic cancer cells by inhibition of the Wnt/PI3K signaling pathways: identification of IL-20 receptor-mediated bystander activity against pancreatic cancer. Mol Ther 11:724–733CrossRefPubMed

43.

Chada S, Mhashilkar AM, Ramesh R, Mumm JB, Sutton RB, Bocangel D, Zheng M, Grimm EA, Ekmekcioglu S (2004) Bystander activity of Ad-mda7: human MDA-7 protein kills melanoma cells via an IL-20 receptor-dependent but STAT3-independent mechanism. Mol Ther 10:1085–1095CrossRefPubMed

44.

Luscher U, Filgueira L, Juretic A, Zuber M, Luscher NJ, Heberer M, Spagnoli GC (1994) The pattern of cytokine gene expression in freshly excised human metastatic melanoma suggests a state of reversible anergy of tumor-infiltrating lymphocytes. Int J Cancer 57:612–619PubMed

45.

Matsuda M, Salazar F, Petersson M, Masucci G, Hansson J, Pisa P, Zhang QJ, Masucci MG, Kiessling R (1994) Interleukin 10 pretreatment protects target cells from tumor- and allo-specific cytotoxic T cells and downregulates HLA class I expression. J Exp Med 180:2371–2376CrossRefPubMed

46.

Kim J, Modlin RL, Moy RL, Dubinett SM, McHugh T, Nickoloff BJ, Uyemura K (1995) IL-10 production in cutaneous basal and squamous cell carcinomas. A mechanism for evading the local T cell immune response. J Immunol 155:2240–2247PubMed

47.

Suzuki T, Tahara H, Narula S, Moore KW, Robbins PD, Lotze MT (1995) Viral interleukin 10 (IL-10), the human herpes virus 4 cellular IL-10 homologue, induces local anergy to allogeneic and syngeneic tumors. J Exp Med 182:477–486CrossRefPubMed

48.

Fortis C, Foppoli M, Gianotti L, Galli L, Citterio G, Consogno G, Gentilini O, Braga M (1996) Increased interleukin-10 serum levels in patients with solid tumours. Cancer Lett 104:1–5CrossRefPubMed

49.

Kozlowski L, Zakrzewska I, Tokajuk P, Wojtukiewicz MZ (2003) Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients. Rocz Akad Med Bialymst 48:82–84PubMed

50.

Toomey D, Harmey J, Condron C, Kay E, Bouchier-Hayes D (1999) Phenotyping of immune cell infiltrates in breast and colorectal tumours. Immunol Invest 28:29–41PubMed

51.

Venetsanakos E, Beckman I, Bradley J, Skinner JM (1997) High incidence of interleukin 10 mRNA but not interleukin 2 mRNA detected in human breast tumours. Br J Cancer 75:1826–1830PubMed

Titel: Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10
verfasst von: Mingzhong Zheng
Dora Bocangel
Blair Doneske
Abner Mhashilkar
Rajagopal Ramesh
Kelly K. Hunt
Suhendan Ekmekcioglu
R. Bryan Sutton
Nancy Poindexter
Elizabeth A. Grimm
Sunil Chada
Publikationsdatum: 01.02.2007
Verlag: Springer-Verlag
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 2/2007
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-006-0175-1

Springer Medizin

Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10

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