Faculty Profiles - KAGAWA Shunsuke

Papers - KAGAWA Shunsuke

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腹壁原発末梢型神経外胚葉性腫瘍(PNET)の1切除例

渡辺信之, 片岡正文, 斎藤信也, 常光洋輔, 香川俊輔, 田中紀章, 難波康男, 漆畑貴行, 久山彰一, 田端雅弘

岡山医学会雑誌 113 ( 3 ) 317 - 317 2001.12

Use of the probasin promoter ARR(2)PB to express Bax in androgen receptor-positive prostate cancer cells

F Andriani, B Nan, J Yu, XY Li, NL Weigel, MJ McPhaul, S Kasper, S Kagawa, BL Fang, RJ Matusik, L Denner, M Marcelli

JOURNAL OF THE NATIONAL CANCER INSTITUTE 93 ( 17 ) 1314 - 1324 2001.9

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL CANCER INSTITUTE

Background: Adenovirus-mediated overexpression of the apoptosis-inducing protein Bax can induce apoptosis in prostate cancer cell lines. Constitutive overexpression of Bax could result in unwanted apoptosis in every site of accidental Bax accumulation in vivo. Therefore, we developed an adenoviral construct (Av-ARR(2)PB-Bax) in which the probasin promoter, modified to contain two androgen response elements, drives Bax expression. This promoter would be expected to limit expression of Bax to cells expressing the androgen receptor. Methods: A variety of androgen receptor (AR)-positive and -negative cell lines of prostatic or nonprostatic origin were infected with Av-ARR2PB-Bax or a control virus, Av-ARR(2)PB-CAT, in which the same promoter drives expression of the chloramphenicol acetyl transferase-reporter gene. Bax expression and apoptosis in vitro were assessed by western blot analysis. Tumor size and apoptosis in vivo were assessed after four weekly injections of Av-ARR(2)PB-Bax or Av-ARR(2)PB-CAT into subcutaneous LNCaP xenografts growing in uncastrated male mice. All statistical tests were two-sided. Results: Bax was overexpressed in an androgen-dependent way in AR-positive cell lines of prostatic origin but not in AR-positive cells of nonprostatic origin or in AR-negative cell lines of either prostatic or nonprostatic origin. The androgen dihydrotestosterone activated apoptosis in LNCaP cells infected with Av-ARR2PB-Bax but not in those infected with Av-ARR(2)-PB-CAT. Av-ARR(2)PB-Bax-injected LNCaP xenograft tumors decreased in tumor size from 34.1 mm(3) (95% confidence interval [CI] = 25.1 mm(3) to 43.1 mm(3)) to 24.6 mm(3) (95% CI = -2.5 mm(3) to 51.7 mm(3)), but the difference was not statistically significant (P = .5). Tumors injected with Av-ARR(2)PB-CAT increased in size, from 28.9 mm(3) (95% CI = 12.7 mm(3) to 45.1 mm(3)) to 206 mm(3) (95% CI = 122 mm(3) to 290 mm(3)) (P = .002) and contained statistically significant more apoptotic cells (23.3% [95% CI = 21.1% to 25.6%] versus 9.5% [95% CI = 8.0% to 11.1]) (P < .001). Conclusions: Av-ARR2PB-Bax induces androgen-dependent therapeutic apoptosis in vitro and in vivo by activating apoptosis in AR-positive cells derived specifically from prostatic epithelium and does not affect nonprostatic cells.

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Accelerated degradation of cellular FLIP protein through the ubiquitin-proteasome pathway in p53-mediated apoptosis of human cancer cells

T Fukazawa, T Fujiwara, F Uno, F Teraishi, Y Kadowaki, T Itoshima, Y Takata, S Kagawa, JA Roth, J Tschopp, N Tanaka

ONCOGENE 20 ( 37 ) 5225 - 5231 2001.8

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Apoptosis is a morphologically distinct form of programmed cell death that plays a major role in cancer treatments. This cellular suicide program is known to be regulated by many different signals from both intracellular and extracellular stimuli. Here we report that p53 suppressed expression of the cellular FLICE-inhibitory protein (FLIP) that potentially blocks apoptotic signaling in human colon cancer cell lines expressing mutated and wild-type p53. In contrast, the expression of the death receptor KILLER/DR5 (TRAIL-R2) had no effect on FLIP expression, although exogenous p53 is known to induce KILLER/DR5 expression. In line with these observations, FLIP-negative cancer cells were sensitive to both p53- and KILLER/DR5-mediated apoptosis, whereas cells containing high levels of FLIP underwent apoptotic cell death when triggered by ectopic p53 expression but not by KILLER/DR5 expression. Treating the cells with a specific inhibitor of the proteasome inhibited the decrease of FLIP by p53, suggesting that p53 enhances the degradation of FLIP via a ubiquitin-proteasome pathway. Thus, the data indicate that p53-mediated downregulation of FLIP may explain the potent sensitization of human cancer cells to the apoptotic suicide program induced by wild-type p53 gene transfer.

DOI： 10.1038/sj.onc.1204673

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Deficiency of caspase-3 in MCF7 cells blocks bax-mediated nuclear fragmentation but not cell death

S Kagawa, J Go, T Honda, TJ McDonnell, SG Swisher, JA Roth, BL Fang

CLINICAL CANCER RESEARCH 7 ( 5 ) 1474 - 1480 2001.5

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Caspase-3 plays a critical role in a proteolytic cascade within the apoptosis signal pathway; this enzyme is commonly activated by numerous death signals and cleaves a variety of important cellular proteins, Using caspase-3-deficient MCF7 cells and clones stably transfected with the caspase-3 gene (MCF7/Casp3), we evaluated the role of caspase-3 in Bax-induced apoptosis, Bax overexpression induced cell death in both parental MCF7 cells and MCF7/Casp3 cells, The introduction of the caspase-3 gene did not change the rate of cell death. Caspase-3-deficient parental MCF7 cells, however, failed to undergo morphological nuclear and DNA fragmentation, whereas MCF7/casp3 cells displayed intact nuclear dismantling and DNA fragmentation. Caspase-3 deficiency, however, did not affect Bax-induced levels of poly(ADP-ribose) polymerase cleavage, caspase-6 activation, and lamin B cleavage, Together, these results suggest that a deficit in caspase-3 is not sufficient to block Bax-induced cell death.

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Antitumor activity and bystander effects of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene

S Kagawa, C He, J Gu, P Koch, SJ Rha, JA Roth, SA Curley, LC Stephens, BL Fang

CANCER RESEARCH 61 ( 8 ) 3330 - 3338 2001.4

Augmenting transgene expression from carcinoembryonic antigen (CEA) promoter via a GAL4 gene regulatory system

PE Koch, ZS Guo, S Kagawa, J Gu, JA Roth, B Fang

MOLECULAR THERAPY 3 ( 3 ) 278 - 283 2001.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC

Though extensively studied, the use of tissue- or cell-type-specific promoters to target transgene expression is hampered by their weak activity. We hypothesized that this problem could be addressed by using a GAL4 gene regulatory system, wherein a weak, tissue-specific promoter would drive expression of the GAL4/VP16 fusion protein (GV16), which in turn would transactivate a minimal synthetic promoter, GAL4/TATA (GT), upstream of a transgene. To test this hypothesis, we constructed adenoviral vectors expressing a IacZ or GV16 gene driven by a carcinoembryonic antigen (CEA) promoter (Ad/CEA-LacZ or Ad/CEA-GV16) and evaluated levels of transgene expression they produced in cultured cells and in subcutaneous tumors after intratumoral administration. In CEA-positive cells, treatment with Ad/CEA-GV16 + Ad/GT-LacZ versus Ad/CEA-LacZ increased transgene expression 20- to 100-fold. In CEA-negative cells, treatment with Ad/CEA-GV16 + Ad/GT-LacZ increased transgene expression to a much lower degree (6- to 8-fold). In addition, analysis of Bax gene-mediated cell death revealed that this system can be used to avoid Bax's toxic effects on CEA-negative cells without compromising its ability to kill CEA-positive cells in vitro and in vivo. Thus, the combination of a tissue-specific promoter with the GAL4 gene regulatory system could be useful for targeting transgene expression.

DOI： 10.1006/mthe.2001.0273

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特集肺癌の診断治療法における最近の進歩 4.化学療法の進歩肺癌の遺伝子治療.

片岡正文, 香川俊輔, 藤原俊義, 田中紀章

肺癌の臨床 4,2,221-230 2001

p53遺伝子を用いた肺癌の遺伝子治療.

香川俊輔, 藤原俊義, 片岡正文, 田中紀章

Lung Cancer Today 1 ,12-16 2001

呼吸器疾患に対する遺伝子治療.

香川俊輔, 藤原俊義, 片岡正文, 田中紀章

外科 63, 1740-1747 2001

Tumor-specific transgene expression from the human telomerase reverse transcriptase promoter enables targeting of the therapeutic effects of the Bax gene to cancers Reviewed

J Gu, S Kagawa, M Takakura, S Kyo, M Inoue, JA Roth, BL Fang

CANCER RESEARCH 60 ( 19 ) 5359 - 5364 2000.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase, which is highly active in immortalized cells and >85% of human cancers but is quiescent in most normal somatic cells. To test the feasibility of using the hTERT promoter to induce tumor-specific transgene expression in cancer gene therapy, we constructed an adenoviral vector expressing a LacZ reporter gene driven by the hTERT core promoter and evaluated its activity in vitro and in vivo. The hTERT promoter could drive high-level expression of LacZ in tumor cells but not in normal cells and normal mouse tissues. Using a binary adenoviral system that can induce Bax gene expression, we showed that induction of the Bax gene expression via the hTERT promoter elicited tumor-specific apoptosis in vitro, suppressed tumor growth in nude mice, and prevented the toxicity of the Bax gene in vitro and in vivo. Thus, the hTERT promoter is apparently a strong and tumor-selective promoter with potential application in targeted cancer gene therapy.

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Antitumor effect of adenovirus-mediated Bax gene transfer on p53-sensitive and p53-resistant cancer lines

S Kagawa, J Gu, SG Swisher, L Ji, JA Roth, D Lai, LC Stephens, BL Fang

CANCER RESEARCH 60 ( 5 ) 1157 - 1161 2000.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Antitumor effects of the proapoptotic Bax gene have been evaluated in vitro and in vivo by a binary adenovirus system expressing the human Bax gene. Overexpression of the Bax gene in cultured cell fines from human lung carcinoma results in caspase activation, apoptosis induction, and cell growth suppression. Intratumoral injection of adenovirus vector expressing the Bax gene suppressed growth of human lung cancer xenografts established in nude mice. Histological examination of tumors from mice treated with the Bax gene demonstrated high levels of Bax expression and extensive apoptosis in tumors. In comparison with the treatment by an adenoviral vector expressing human p53, the Bax gene can effectively suppress tumor growth in both p53-sensitive and p53-resistant human lung carcinoma cell lines. Toxicity was not detected in liver and other systems in animals treated intralesionally with the Bax gene. Therefore, our results suggest that the Bax gene may be useful in cancer treatment.

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Adenoviral Bak overexpression mediates caspase-dependent tumor killing

A Pataer, BL Fang, R Yu, S Kagawa, KK Hunt, TJ McDonnell, JA Roth, SG Swisher

CANCER RESEARCH 60 ( 4 ) 788 - 792 2000.2

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

One of the most promising strategies in cancer gene therapy is adenoviral transfer of proapoptotic genes. We therefore evaluated the novel strategy of adenovirally overexpressing the proapoptotic Bak gene. Our results showed marked apoptosis in cancer cells in vivo and in vitro after Bak gene transfer via a binary adenoviral vector system. This effect was not seen in a caspase 3-defective cell Line (MCF-7) and was abrogated in Bah-sensitive tumors after administration of the caspase inhibitor z-DEVD-fmk. Our results suggest that adenoviral-mediated overexpression of Bak provides a novel therapeutic strategy for cancer therapy, but this process appears to be caspase dependent.

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A binary adenoviral vector system for expressing high levels of the proapoptotic gene bax

S Kagawa, SA Pearson, L Ji, K Xu, TJ McDonnell, SG Swisher, JA Roth, B Fang

GENE THERAPY 7 ( 1 ) 75 - 79 2000.1

Language：English Publishing type：Research paper (scientific journal) Publisher：STOCKTON PRESS

The bax gene plays a critical role in signaling apoptosis and expression through gene transfer may be valuable in the treatment of a variety of apoptosis-related diseases such as cancer. However, constructing an adenoviral vector expressing a bax gene driven by a constitutive promoter has been difficult, presumably because of the gene's high proapoptotic activity. Here we report a system that induces the expression of the bax gene safely by adenovirus-mediated gene cotransfer. Briefly, the system involves an adenoviral vector containing a human bax cDNA driven by a synthetic promoter consisting of five GAL4-binding sites and a TATA box (GT). This vector expresses a minimal background level of bax protein in cultured mammalian cells thus preventing apoptosis of packaging cells. However, expression of the bax gene can be induced substantially in vitro and in vivo by transferring it into target cells along with an adenoviral vector expressing the transactivator, fusion protein GAL4/VP16. Extensive apoptosis was observed after induction of the bax gene both in cultured human lung carcinoma cells and in the livers of Balb/c mice. Our results suggest that this GAL4 gene regulatory system provides an alternative approach to constructing viral vectors that express potentially toxic genes.

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Induction of differentiation-dependent apoptosis in human esophageal squamous cell carcinoma by adenovirus-mediated p21sdi1 gene transfer.

Kadowaki Y, Fujiwara T, Fukazawa T, Shao J, Yasuda T, Itoshima T, Kagawa S, Hudson LG, Roth JA, Tanaka N

Clin Cancer Res. 2000

Overexpression of the p21(sdi1) gene induces senescence-like state in human cancer cells: implication for senescence-directed molecular therapy for cancer

S Kagawa, T Fujiwara, Y Kadowaki, T Fukazawa, R Sok-Joo, JA Roth, N Tanaka

CELL DEATH AND DIFFERENTIATION 6 ( 8 ) 765 - 772 1999.8

Language：English Publishing type：Research paper (scientific journal) Publisher：STOCKTON PRESS

Normal cells in a culture enter a nondividing state after a finite number of population doubling, which is termed replicative senescence, whereas cancer cells have unlimited proliferative potential and are thought to exhibit an immortal phenotype by escaping from senescence. The p21 gene (also known as sdi1), which encodes the cyclin-dependent kinase inhibitor, is expressed at high levels in senescent cells and contributes to the growth arrest. To examine if the p21(sdi1) gene transfer could induce senescence in human cancer cells, we utilized an adenoviral vector-based expression system and four human cancer cell lines differing in their p53 status. Transient overexpression of p21(sdi1) on cancer cells induced quiescence by arresting the cell cycle at the G(1) phase and exhibited morphological changes, such as enlarged nuclei as well as a flattened cellular shape, specific to the senescence phenotype. We also showed that p21(sid1)-transduced cancer cells expressed beta-galactosidase activity at pH 6.0, which is known to be a marker of senescence. Moreover, the polymerase chain reaction-based assay demonstrated that levels of telomerase activity were significantly lower in p21(sdi1)-expressing cells compared to parental cancer cells. These observations provide the evidence that p21(sdi1) overexpression could induce a senescence-like state and reduce telomerase activity in human cancer cells, suggesting that these novel p21(sdi1) functions may have important implications for anticancer therapy.

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Overexpression of Bcl-2 in bladder cancer cells inhibits apoptosis induced by cisplatin and adenoviral-mediated p53 gene transfer

Miyake Hideaki, Hanada Norihisa, Nakamura Hideo, Kagawa Shunsuke, Fujiwara Toshiyoshi, Hara Isao, Eto Hiroshi, Gohji Kazuo, Arakawa Soichi, Kamidono Sadao, Saya Hideyuki

Oncogene 16 ( 7 ) 933 - 943 1998.2

Language：English

<p>To investigate the effects of the expression of Bcl-2 protein in bladder cancer on the apoptosis induced by cisplatin or adenoviral-mediated p53 gene (Ad5CMV-p53) transfer, we transfected the bcl-2 gene into KoTCC-1, a human bladder cancer cell line that does not express the Bcl-2 protein. The Bcl-2-transfected KoTCC-1 (KoTCC-1/B) exhibited significantly higher resistance to both cisplatin and Ad5CMV-p53 transfer than did either the parental KoTCC-1 (KoTCC-1/P) or the vector-only transfected cell line (KoTCC-1/C). The flow cytometric analysis of the propidium iodide-stained nuclei and DNA fragmentation analysis after cisplatin or Ad5CMV-p53 treatment revealed DNA degradation in both KoTCC-1/P and KoTCC-1/C, whereas KoTCC1/B showed a marked inhibition of DNA degradation. Following the treatment with cisplatin or Ad5CMV-p53, the accumulation of p53 protein was highly detectable for a long period in KoTCC-1/B compared to that in KoTTC-1/P and KoTCC-1/C. Furthermore, the cisplatin and Ad5CMV-p53 treatments each reduced the volume of the subcutaneous tumors established in nude mice formed by KoTCC-1/P or KoTCC-1/C; in contrast, their reductive effects on the tumors formed by KoTCC-1/

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p53遺伝子導入によるがん治療の可能性 (特集p53の生理作用--その多様性の源に迫る)

藤原俊義, 香川俊輔, 西崎正彦

細胞工学 16 ( 4 ) 556 - 563 1997.4

Novel combination therapy for human colon cancer with adenovirus- mediated wild-type p53 gene transfer and DNA-damaging chemotherapeutic agent Reviewed

Nobuyuki Ogawa, Toshiyoshi Fujiwara, Shunsuke Kagawa, Masahiko Nishizaki, Yoshinori Morimoto, Tohru Tanida, Akio Hizuta, Tutsuji Yasuda, Jack A. Roth, Noriaki Tanaka

International Journal of Cancer 73 ( 3 ) 367 - 370 1997

Language：English Publishing type：Research paper (scientific journal)

Alteration of the wild-type (wt) p53 gene by mutation, deletion or re- arrangement is a major factor in the development of human colon cancer. Recent studies have demonstrated that p53 might be an essential component of the apoptotic pathway triggered by DNA-damaging stimuli such as chemotherapeutic agents and ionizing radiation. We examined the anti-tumor effects of adenovirus-mediated wt-p53 gene transfer in combination with a chemotherapeutic drug on the human colon cancer cell line WiDr, which is homozygous for a mutation in the p53 gene. Treatment with the chemotherapeutic drug cisplatin following infection with a replication- deficient, recombinant adenoviral vector expressing wt-p53 (termed AdCMVp53) significantly suppressed the growth of WiDr cells compared to single treatments alone. To evaluate the in vivo efficacy of AdCMYp53 and cisplatin given sequentially, WiDr cells were inoculated s.c. in nu/nu mice. After 3 days, AdCMVp53 was injected s.c. into the area where tumor cells were implanted, followed by i.p. administration of cisplatin. Analysis of initial growth inhibition at 21 days demonstrated a profound therapeutic cooperativity, though administration of either AdCMVp53 or cisplatin alone was followed only by a slowing of growth. Our results suggest that gene therapy using wt-p53-expressing adenovirus in combination with a chemotherapeutic DNA-damaging drug could be a useful strategy for treating human colon cancer.

DOI： 10.1002/(SICI)1097-0215(19971104)73:3<367::AID-IJC11>3.0.CO;2-A

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p53 expression overcomes p21WAF1/CIP1-mediated G1 arrest and induces apoptosis in human cancer cells Reviewed

Shunsuke Kagawa, Toshiyoshi Fujiwara, Akio Hizuta, Tatsuji Yasuda, Wei-Wei Zhang, Jack A. Roth, Noriaki Tanaka

Oncogene 15 ( 16 ) 1903 - 1909 1997

Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Publishing Group

The p21WAF1/CIP1 gene, which encodes a cyclin-dependent kinase inhibitor, may be critical for tumor suppressor gene p53-induced cell cycle arrest. The p53 gene is known to regulate G1 checkpoint, which can either induce G1 arrest or initiate apoptosis. To directly examine the role of p21WAF1/CIP1 in the control of p53 function, we have introduced human p21WAF1/CIP1 gene into a p53-deficient human non-small cell lung cancer cell line H1299 using a p21WAF1/CIP1-expressing adenoviral vector (AdCMVp21). Infection with AdCMVp21 resulted in high levels of p21WAF1/CIP1 expression and significantly suppressed the growth of H1299 cells through the G1 arrest of the cell cycle. In contrast, transient expression of the wild-type p53 gene by a recombinant adenoviral vector (AdCMVp53) in H1299 cells induced apoptotic cell death and resulted in a rapid loss of cell viability. We then examined the effects of combined infection with AdCMVp21 and AdCMVp53 on H1299 cells to explore the dominant function of these molecules. Interestingly, introduction of exogenous p53 overcame p21WAF1/CIP1-mediated cell cycle arrest at G1 and induced apoptosis, although viral-transduced p21WAF1/CIP1 expression level was unaffected. These observations suggest that p53 expression converts a p21WAF1/CIP1-mediated growth arrest into apoptosis. The result was repeated with two additional human colon adenocarcinoma cell lines with the different p53 status, mutant p53-expressing DLD-1 and wild-type p53-expressing LoVo, suggesting that this phemonenon is a general event among human cancer cells. Thus, p53-mediated apoptotic pathway is dominant over the growth arrest pathway, indicating that p53 may be an essential upstream mediator of p21WAF1/CIP1 in the regulation of a cell process leading either to growth arrest or to apoptotic suicide. © 1997 Stockton Press All rights reserved.

DOI： 10.1038/sj.onc.1201362

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The changing pattern of platelet count after gastrointestinal surgery according to the healing stage

Hitoshi Takeuchi, Eiji Konaga, Masahiko Kuinose, Masahiko Nishizaki, Takayoshi Murakami, Shunsuke Kagawa, Takashi Yoshioka, Yuhji Kanaoka, Kohji Tanakaya, Yoshimasa Yasui, Kazuo Tanemoto, Masaaki Kashitani, Genso Kobayashi

Japanese Journal of National Medical Services 48 ( 7 ) 483 - 487 1994

Language：English Publishing type：Research paper (scientific journal)

In order to speculate the role of platelet in the wound healing, we examined platelet count in 27 patients who showed anastomotic leakage after gastrointestinal surgery. Thirty-nine patients who did not show leakage were served as control. Results were as follows: (1) The maximal values of platelet after surgery correlated with the surgical invasion. (2) Platelet count showed biphasic pattern after surgery. At first platelet count decreased. Then the count increased and reached its maximal values in the 2nd week in the control group. However, the maximal values were obtained in the 3rd week in the case of the patients with leakage. After that, platelet count decreased to normal level in healing stage. This tendency was more prominent in early leakage group than delayed leakage group. (3) The changing pattern of platelet count after surgery did not coincide with that of white cell count. White cell count was normal in 10 out of 27 (37%) in leakage cases. However, the platelet count in these cases increased in 9 out of 10 (90%). Therefore, it is concluded that the maximum of platelet after surgery reflects surgical invasion well. The changing pattern of platelet count after surgery is useful in speculating healing stage and detecting anastomotic leakage early. © 1994, Japanese Society of National Medical Services. All rights reserved.

DOI： 10.11261/iryo1946.48.483

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