肝癌細胞に対するmda-7/IL-24の腫瘍抑制効果とシグナル伝達

加藤 久美子; 佐伯 知行; 山崎 洋次

doi:10.5833/jjgs.38.1280

The Tumor Suppressor Activity and Signaling Pathways of Mda-7/IL-24 in Hepatic Cancer Cells

Kumiko Kato, Tomoyuki Saeki, Youji Yamazaki

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Keywords: apoptosis, mda-7, IL-24, hepatic cancer cell, gene therapy

JOURNAL FREE ACCESS

2005 Volume 38 Issue 8 Pages 1280-1287

DOI https://doi.org/10.5833/jjgs.38.1280

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Published: 2005 Received: February 23, 2005 Available on J-STAGE: June 08, 2011 Accepted: - Advance online publication: - Revised: -
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Date of correction: June 08, 2011 Reason for correction: - Correction: CITATION Details: Wrong : 1) Jiang H, Lin JJ, Su ZZ et al: Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 11: 2477-2486, 1995
2) Fisher PB, Grant S: Effects of interferon on differentiation of normal and tumor cells. Pharmacol Ther 27: 143-166, 1985
3) Jiang H, Su ZZ, Lin JJ et al: The melanoma differentiation associated gene mda-7 suppresses cancer cell growth. Proc Natl Acad Sci USA 93: 9160-9165, 1996
4) Guarini L, Graham GM, Jiang H et al: Modulation of the antigenic phenotype of human melanoma cells by differentiation-inducing and growth-suppressing agents. Pigment Cell Res 2: 123-131, 1992
5) Huang F, Adelman J, Jiang H et al: Differentiation induction subtraction hybridization (DISH): a strategy for cloning genes displaying differential expression during growth arrest and terminal differentiation. Gene 236: 125-131, 1999
6) Jiang H, Lin J, Su ZZ et al: The melanoma differentiation-associated gene mda-6, which encodes the cyclin-dependent kinase inhibitor p21, is differentially expressed during growth, differentiation and progression in human melanoma cells. Oncogene 10: 1855-1864, 1995
7) Jiang H, Lin J, Young SM et al: Cell cycle gene expression and E 2 F transcription factor complexes in human melanoma cells induced to terminally differentiate. Oncogene 11: 1179-1189, 1995
8) Levedeva I, Su Z, Chang Y et al: The cancer suppressinggrowth gene mda-7 induces apoptosis selectively in human melanoma cells. Oncogene 21: 708-718, 2002
9) Mhashilkar AM, Schrock RD, Hindi M et al: Melanoma differentiation associated gene-7 (mda7): a novel anti-tumor gene for cancer gene therapy. Mol Med 7: 271-282, 2001
10) Saeki T, Mhashilkar AM, Chada S et al: Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro. Gene Ther 7: 2051-2057, 2000
11) Su ZZ, Madireddi MT, Lin JJ et al: The canscer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mouse. Proc Natl Acad Sci USA 95: 14400-14405, 1998
12) Sarkar D, Su ZZ, Lebedeva IV et al: 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 p 38 MAPK. Proc Natl Acad Sci USA 99: 10054-10059, 2002
13) Madireddi MT, Su ZZ, Young CS et al: Mda-7, a novel melanoma differentiation associated gene with promise for cancer gene therapy. Adv Exp Med Biol 465: 239-261, 2000
14) Soo C, Shaw WW, Freimiller E et al: Cutaneous rat wounds express C49a, a novel gene with homology to the human melanoma differentiation associated gene, mda-7. J Cell Biochem 74: 1-10, 1999
15) Pataer A, Vorburger SA, Barber GN et al: 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: 2239-2243, 2002
16) Balachandran S, Kim CN, Yeh WC et al: Activation of the dsRNA-dependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling. EMBO J 17: 6888-6902, 1998
17) Huang EY, Madireddi MT, Gopalkrishnan RV et al: 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: 7051-7063, 2001
18) Kotenko SV: The family of IL-10-related cytokines and their receptors: related, but to what extent? Cytokine Growth Factor Rev 13: 223-240, 2002
20) Yamashita Y, Shimada M, Hasegawa H et al: Electroporation-mediated interleukin-12 gene therapy for hepatocellular carcinoma in the mice model. Cancer Res 61: 1005-1012, 2001
21) Ohashi M, Kanai F, Tateishi K et al: Target gene therapy for alpha-fetoprotein-producing hepato-cellular carcinoma by E 1 B 55 k-attenuated adenovirus. Biochem Biophys Res Commun 282: 529-535, 2001
22) Caudell EG, Mumm JB, Poindexter N et al: The protein product of the tumor suppressor gene melanoma differentiation-associated gene 7, exhibits immunostimulatory activity and is designated IL-24. J Immunol 168: 6041-6046, 2002
23) Sauane M, Gopalkrishnan RV, Lebedeva I et al: Mda-7⁄IL-24 induces apoptosis of diverse cancer cell lines through JAK⁄STAT-independent pathways.J Cell Physiol 196: 334-345, 2003
24) Sieger KA, Mhashilkar AM, Stewart A et al: The tumor suppressor activity of MDA-7⁄IL-24 is mediated by intracellular protein expression in NSCLC cells. Mol Ther 9: 355-367, 2004
25) Saeki T, Mhashilkar A, Swanson X et al: Inhibition of human lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo. Oncogene 21: 4558-4566, 2002
26) Tsujimoto Y: Cell death regulation by the Bcl-2 protein family in the mitochondria. J Cell Physiol 195: 158-167, 2003
27) Schuler M, Green DR: Mechanisms of p53-dependent apoptosis. Biochem Soc Trans 29: 684-688, 2001
28) Zimmermann KC, Bonzon C, Green DR: The machinery of programmed cell death. Pharmacol Ther 92: 57-70, 2001
29) Saelens X, Kalai M, Vandenabeele P: Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-alpha phosphorylation. J Biol Chem 276: 41620-41628, 2001
30) Vattem KM, Staschke KA, Wek RC: Mechanism of activation of the double-stranded-RNA-dependent protein kinase, PKR: role of dimerization and cellular localization in the stimulation of PKR phosphorylation of eukaryotic initiation factor-2 (eIF2). Eur J Biochem 268: 3674-3684, 2001
31) Dumoutier L, Leemans C, Lejeune D et al: Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J Immunol 167: 3545-3549, 2001
32) Wang M, Tan Z, Zhang R et al: Interleukin 24 (MDA-7⁄MOB-5) signals through two heterodimeric receptors, IL-22R1⁄IL-20R2 and IL-20 R1⁄IL-20R2. J Biol Chem 277: 7341-7347, 2002

Right : 1) Jiang H, Lin JJ, Su ZZ et al: Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 11: 2477-2486, 1995
2) Fisher PB, Grant S: Effects of interferon on differentiation of normal and tumor cells. Pharmacol Ther 27: 143-166, 1985
3) Jiang H, Su ZZ, Lin JJ et al: The melanoma differentiation associated gene mda-7 suppresses cancer cell growth. Proc Natl Acad Sci USA 93: 9160-9165, 1996
4) Guarini L, Graham GM, Jiang H et al: Modulation of the antigenic phenotype of human melanoma cells by differentiation-inducing and growth-suppressing agents. Pigment Cell Res 2: 123-131, 1992
5) Huang F, Adelman J, Jiang H et al: Differentiation induction subtraction hybridization (DISH): a strategy for cloning genes displaying differential expression during growth arrest and terminal differentiation. Gene 236: 125-131, 1999
6) Jiang H, Lin J, Su ZZ et al: The melanoma differentiation-associated gene mda-6, which encodes the cyclin-dependent kinase inhibitor p21, is differentially expressed during growth, differentiation and progression in human melanoma cells. Oncogene 10: 1855-1864, 1995
7) Jiang H, Lin J, Young SM et al: Cell cycle gene expression and E 2 F transcription factor complexes in human melanoma cells induced to terminally differentiate. Oncogene 11: 1179-1189, 1995
8) Levedeva I, Su Z, Chang Y et al: The cancer suppressinggrowth gene mda-7 induces apoptosis selectively in human melanoma cells. Oncogene 21: 708-718, 2002
9) Mhashilkar AM, Schrock RD, Hindi M et al: Melanoma differentiation associated gene-7 (mda7): a novel anti-tumor gene for cancer gene therapy. Mol Med 7: 271-282, 2001
10) Saeki T, Mhashilkar AM, Chada S et al: Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro. Gene Ther 7: 2051-2057, 2000
11) Su ZZ, Madireddi MT, Lin JJ et al: The canscer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mouse. Proc Natl Acad Sci USA 95: 14400-14405, 1998
12) Sarkar D, Su ZZ, Lebedeva IV et al: 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 p 38 MAPK. Proc Natl Acad Sci USA 99: 10054-10059, 2002
13) Madireddi MT, Su ZZ, Young CS et al: Mda-7, a novel melanoma differentiation associated gene with promise for cancer gene therapy. Adv Exp Med Biol 465: 239-261, 2000
14) Soo C, Shaw WW, Freimiller E et al: Cutaneous rat wounds express C49a, a novel gene with homology to the human melanoma differentiation associated gene, mda-7. J Cell Biochem 74: 1-10, 1999
15) Pataer A, Vorburger SA, Barber GN et al: 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: 2239-2243, 2002
16) Balachandran S, Kim CN, Yeh WC et al: Activation of the dsRNA-dependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling. EMBO J 17: 6888-6902, 1998
17) Huang EY, Madireddi MT, Gopalkrishnan RV et al: 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: 7051-7063, 2001
18) Kotenko SV: The family of IL-10-related cytokines and their receptors: related, but to what extent? Cytokine Growth Factor Rev 13: 223-240, 2002
20) Yamashita Y, Shimada M, Hasegawa H et al: Electroporation-mediated interleukin-12 gene therapy for hepatocellular carcinoma in the mice model. Cancer Res 61: 1005-1012, 2001
21) Ohashi M, Kanai F, Tateishi K et al: Target gene therapy for alpha-fetoprotein-producing hepato-cellular carcinoma by E 1 B 55 k-attenuated adenovirus. Biochem Biophys Res Commun 282: 529-535, 2001
22) Caudell EG, Mumm JB, Poindexter N et al: The protein product of the tumor suppressor gene melanoma differentiation-associated gene 7, exhibits immunostimulatory activity and is designated IL-24. J Immunol 168: 6041-6046, 2002
23) Sauane M, Gopalkrishnan RV, Lebedeva I et al: Mda-7/IL-24 induces apoptosis of diverse cancer cell lines through JAK/STAT-independent pathways.J Cell Physiol 196: 334-345, 2003
24) Sieger KA, Mhashilkar AM, Stewart A et al: The tumor suppressor activity of MDA-7/IL-24 is mediated by intracellular protein expression in NSCLC cells. Mol Ther 9: 355-367, 2004
25) Saeki T, Mhashilkar A, Swanson X et al: Inhibition of human lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo. Oncogene 21: 4558-4566, 2002
26) Tsujimoto Y: Cell death regulation by the Bcl-2 protein family in the mitochondria. J Cell Physiol 195: 158-167, 2003
27) Schuler M, Green DR: Mechanisms of p53-dependent apoptosis. Biochem Soc Trans 29: 684-688, 2001
28) Zimmermann KC, Bonzon C, Green DR: The machinery of programmed cell death. Pharmacol Ther 92: 57-70, 2001
29) Saelens X, Kalai M, Vandenabeele P: Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-alpha phosphorylation. J Biol Chem 276: 41620-41628, 2001
30) Vattem KM, Staschke KA, Wek RC: Mechanism of activation of the double-stranded-RNA-dependent protein kinase, PKR: role of dimerization and cellular localization in the stimulation of PKR phosphorylation of eukaryotic initiation factor-2 (eIF2). Eur J Biochem 268: 3674-3684, 2001
31) Dumoutier L, Leemans C, Lejeune D et al: Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J Immunol 167: 3545-3549, 2001
32) Wang M, Tan Z, Zhang R et al: Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20 R1/IL-20R2. J Biol Chem 277: 7341-7347, 2002

Abstract

Purpose: Mda-7/IL-24 is a unique cytokine gene belonging to the IL-10 family. Adenoviral-mediated gene transfer of mda-7/IL-24 induces growth suppression and apoptosis selectively in a wide range of cancer cell lines without causing cytotoxity to normal cells. We studied the anti tumor effect and signaling pathways of mda-7/IL-24 in human hepatic cancer cell lines in vitro. Materials and Methods: Overexpression of MDA-7 by a replication-incompetent adenovirus (Ad-mda-7) in human hepatic cancer cell lines, i. e., HepG2 (p53-wild type) and Hep3B (p53-deleted type), was evaluated by immunochemistry and Western blot analysis. Cell proliferation was assayed by a dye exclusion test. Apoptosis signaling proteins (PARP, CASPASE, and BAX) and the JAK/STAT pathway were evaluated by Western blot analysis. Results: Ad-mda-7 inhibited growth in both cell lines 72 hours after transduction (p<0.05). MDA-7 and cleaved PARP expressions were up-regulated after 72 hours in both cell lines. Up-regulation of BAX expression was observed in HepG2 cells, while no difference was observed in Hep3B cells. Cleaved CASPASE-8 expression was detected in both cell lines, and pSTAT3 expressed in HepG2 cells. Conclusions: Mda-7/IL-24 effectively induced apoptosis in hepatic cell lines. The anti tumor effect was proved to occur in p53 and Bax independently and through the activation of caspase cascade pathways. Activation of STAT3 could be involved in the apoptosis pathway.

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