New strategy for gynecologic cancer targeting of membrane-bound protease

膜结合蛋白酶靶向妇科癌症的新策略

• 批准号: 16591654
• 负责人: KIKKAWA Fumitaka
• 金额: $ 2.37万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591654/
• 关键词: Ovarian cancer; Uterine endometrial cancer; Uterine cervical cancer; aminopeptidase; drug-resistance; metastasis; angiogenesis; substrate-control; CD26; CD13; アポトーシス; 放射線感受性; パクリタキセル; APN; IRAP; APA; ATIR; 予後; 転移・浸潤; カドヘリン

In the present study, we examined the involvement of membrane-bound aminopeptidase in the inhibitory or progressive effect of uterine and ovarian cancer aiming for new therapeutic strategy. We focused on APN/CD13, DPPIV/CD26, IRAP/PLAP, NEP/CD10, and APA as aminopeptidases. Our current findings are as follows. 1) In ovarian cancer cells, DPPIV/CD26 and NEP/CD10 induced the decreased invasiveness, enhanced sensitivity to paclitaxel, and decreased formation of peritoneal metastasis using a mouse-dissemination model. 2) In addition, DPPIV/CD26 induced mesenchymal-epithelial transition (MET) in ovarian cancer cells. 3) As the mechanisms, these aminopeptidases enzymatically degraded SDF-la or Endothelin, which stimulated metastasis and the resistance to anti-neoplastic agents in ovarian cancer. 4) Conversely, the expression of APN/CD13 induced cell-invasiveness and the resistance to paclitaxel in ovarian cancer. Moreover, the inhibition of APN/CD13 using bestatin or siRNA technique resulted in upregulation of sensitivity to paclitaxel and decreased peritoneal metastasis in animal model. 5) Similarly, in uterine cervical cancer cells, the expression of APN/CD13 was involved in enhanced metastatic potential during irradiation and the treatment with bestatin reversed this effect. 6) In uterine endometrial cancer cells, the expression of IRAP/PLAP was involved in the resistance to carboplatin or paclitaxel, and the siRNA specific for IRAP/PLAP reversed the chemosensitivities to these agents. 7) In ovarian cancer, angiotensin-II plays a crucial role in the angiogenesis and the formation of peritoneal dissemination via ATR1. We found that the treatment with an antagonist specific for ATR1 reverse these effects suggesting that it may be useful as a new therapeutic agent.

在本研究中，我们研究了膜结合的氨基肽酶参与子宫和卵巢癌的抑制作用或逐步效应，旨在采用新的治疗策略。我们专注于APN/CD13，DPPIV/CD26，IRAP/PLAP，NEP/CD10和APA作为氨基肽酶。我们目前的发现如下。 1）在卵巢癌细胞中，DPPIV/CD26和NEP/CD10诱导了侵入性降低，对紫杉醇的敏感性增强，并使用小鼠 - 隔离模型降低了腹膜转移的形成。 2）此外，DPPIV/CD26在卵巢癌细胞中诱导间充质 - 上皮过渡（MET）。 3）作为机制，这些氨基肽酶会酶降解的SDF-LA或内皮素，它们刺激转移以及对卵巢癌中抗肿瘤剂的抗性。 4）相反，APN/CD13的表达诱导细胞侵入性和对卵巢癌紫杉醇的抗性。此外，使用BestAtin或siRNA技术对APN/CD13的抑制导致对紫杉醇的敏感性上调，并减少动物模型中腹膜转移。 5）类似地，在子宫宫颈癌细胞中，APN/CD13的表达参与了辐射过程中的转移潜力增强，而用Bestatin的治疗则反转了这种作用。 6）在子宫子宫内膜癌细胞中，IRAP/PLAP的表达参与了对卡铂或紫杉醇的抗性，而针对IRAP/PLAP的siRNA则与这些药物的化学敏感性相反。 7）在卵巢癌中，血管紧张素-II在通过ATR1的血管生成和腹膜传播形成中起着至关重要的作用。我们发现用特异性拮抗剂的ATR1治疗逆转了这些作用，这表明它可能是一种新的治疗剂。

项目成果

Survival rates o patients with choriocarcinoma treated with chemotherapy without hysterectomy : effects o anticancer agents on subsequent births.

接受化疗但未进行子宫切除术的绒毛膜癌患者的存活率：抗癌药物对后续出生的影响。

• 发表时间: 2004
• 期刊: Gynecol Oncol 93(2)
• 作者: Goto S;Ino K;Mitsui T;Kikkawa F;Suzuki T;Nomura S;Mizutani S
• 通讯作者: Mizutani S

Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cells b overexpression ofAP-2alpha.

AP-2α过表达抑制卵巢癌细胞的侵袭和腹膜癌变。

• 发表时间: 2004
• 期刊: Oncogene 23(32)
• 作者: Sumigama S;Ito T;Kajiyama H;Shibata K;Tamakoshi K;Kikkawa F;Williams T;Tainsky MA;Nomura S;Mizutani S
• 通讯作者: Mizutani S

Insulin stimulates placental leucine aminopeptidase/oxytocinase/insulin-regulated membrane aminopeptidase expression in BeWo choriocarcinoma cells.

胰岛素刺激 BeWo 绒毛膜癌细胞中胎盘亮氨酸氨肽酶/催产素酶/胰岛素调节的膜氨肽酶的表达。

• 发表时间: 2004
• 期刊: Regul Pept. 117(3)
• 作者: Nakata M;Nomura S;Ikoma Y;Sumigama S;Shido F;Ito T;Okada M;Kikkawa F
• 通讯作者: Kikkawa F

Placental leucine aminopeptidase (P-LAP) and glucose transporter 4 (GLUT4) expression in benign, borderline, and malignant ovarian epithelia

• DOI: 10.1016/j.ygyno.2005.03.043
• 发表时间: 2005-07-01
• 期刊: GYNECOLOGIC ONCOLOGY
• 影响因子: 4.7
• 作者: Shibata, K;Kajiyama, H;Kikkawa, F
• 通讯作者: Kikkawa, F

Stromal cell-derived factor-1alpha-induced cell proliferation and its possible regulation by CD26/dipeptidyl peptidase IV in endometrial adenocarcinoma.

子宫内膜腺癌中基质细胞衍生因子 1α 诱导的细胞增殖及其可能受 CD26/二肽基肽酶 IV 的调节。

• 发表时间: 2004
• 期刊: Int J Cancer 110
• 作者: Shibata K;et al.;Ino K et al.;Shibata K et al.;Mizokami Y et al.;Kikkawa F et al.;Mizokami Y et al.
• 通讯作者: Mizokami Y et al.