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

加藤久美子, 佐伯知行, 山崎洋次

著者情報

ジャーナルフリー

2005 年 38 巻 8 号 p. 1280-1287

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

詳細

発行日: 2005 年受付日: 2005/02/23 J-STAGE公開日: 2011/06/08 受理日: - 早期公開日: - 改訂日: -
訂正情報
訂正日: 2011/06/08 訂正理由: - 訂正箇所: 引用文献情報訂正内容: 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

抄録

はじめに: mda-7/IL-24はIL-10ファミリーに属するサイトカインである. mda-7を発現したアデノウイルスベクター (Ad-mda-7) を用いて癌細胞にmda-7遺伝子を導入すると癌特異的に増殖抑制とアポトーシスを誘導することがさまざまな癌細胞で証明されている. 本実験ではAd-mda-7が肝癌細胞株に及ぼす腫瘍抑制効果およびシグナル伝達機構をin vitroで検討した. 方法: Ad-mda-7をHepG2 (p53野生型) およびHep3B (p53欠失型) に感染させ, 免疫染色およびWestern blot解析を用いて細胞内MDA-7の発現を検出し, trypan-blue染色法で生存曲線を作成した. さらに, Ad-ma-7感染後に発現しているアポトーシス関連蛋白 (PARP, CASPASE, BAX) およびJAK/STAT 蛋白をWestern blot解析で検出した. 結果: 両細胞においてAd-mda-7感染72時間以後に増殖抑制を有意に認めた (p<0.05). 感染72時間以後に両細胞でMDA-7の発現およびcleaved-PARPの増強を検出した. BAXの発現はHepG2で増加していたがHep3Bでは増加を認めなかった. cleaved-caspase8の発現は両細胞で増強し, p-STAT3はHepG2 で増強していた. 結論: mda-7/IL-24は効率的に肝癌細胞株にアポトーシスを誘導した. その誘導経路はp53およびBAXに非依存的でありcaspase活性化経路によると考えられた. STAT3もまたアポトーシスに関与していると考えられた.

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