COBRE: NDSU: PROJECT 3: MMP-9 IN APOPTOSIS OF PROSTATE CANCEL CELLS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 基质金属蛋白酶（MMPs）是肿瘤治疗的重要靶点。但最近的 MMP抑制剂的临床试验令人失望。某些MMPs可调节细胞凋亡 信号通路和使肿瘤细胞对凋亡信号敏感。这些MMP的抑制将 促进肿瘤细胞存活，这种作用可能抵消抑制肿瘤细胞增殖的有益活性。 转移基质金属蛋白酶-9（MMP-9）的表达显著增加， 恶性前列腺癌除了能够切割胶原和基底膜外， MMP-9还切割和激活多功能细胞因子 TGF-β。 TGF-β（在哺乳动物中具有三种同种型：TGF-β 1、TGF-β 2、TGF-β 3）是一种重要的调节因子， 正常和恶性前列腺。TGF-β 1在某些前列腺癌中诱导细胞凋亡 细胞，TGF-β 2阻断细胞凋亡。通过激活TGF-β的所有三种亚型，MMP-9可能 对前列腺癌细胞凋亡的不同净效应取决于TGF-β亚型、其受体和下游信号分子的表达状态。存在一个临界 需要确定MMP-9对前列腺癌细胞凋亡的影响。据推测， 抑制MMP-9将有益于MMP-9介导的TGF-β活化 在癌细胞中的抗凋亡作用。 根据TGF-β信号传导机制的状态选择合适的患者可能是 这对于未来评估MMP-9抑制剂治疗效果的临床试验至关重要。的 本研究的目的是明确MMP-9在前列腺癌细胞凋亡中的作用，以及MMP-9如何影响前列腺癌细胞凋亡。 MMP-9对前列腺癌细胞凋亡的影响沿着前列腺癌进展。在 本课题的完成，我们希望能够阐明MMP-9在细胞凋亡调控中的作用， 前列腺癌以及这种作用如何与TGF-β信号的变化有关 在前列腺癌发展的不同阶段

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Matrix metalloproteinases (MMPs) are promising targets for cancer therapy. However, recent clinical trials of MMP inhibitors have been disappointing. Certain MMPs may regulate apoptosis signaling pathways and sensitize tumor cells to apoptotic signals. Inhibition of these MMPs will promote tumor cell survival and this effect may offset the beneficial activity in inhibition of metastasis. Matrix metalloproteinase-9 (MMP-9) expression is significantly increased in malignant prostate cancers. In addition to its ability to cleave collagens and basement membrane components, MMP-9 also cleaves and activates the multifunctional cytokine TGF-¿. TGF-¿ (having three isoforms in mammals: TGF-¿1, ¿2, ¿3) is an important regulator of normal and malignant prostate. While TGF-¿1 induces apoptosis in certain prostate cancer cells, TGF-¿2 blocks apoptosis. By activating all three isoforms of TGF-¿, MMP-9 may have different net effect on prostate cancer apoptosis depending on the status of expression of TGF-¿ isoforms, their receptors, and the downstream signaling molecules. There is a critical need to determine the effects of MMP-9 on apoptosis in prostate cancer. Presumable, inhibition of MMP-9 will be beneficial in patients where MMP-9-mediated TGF-¿ activation has an anti-apoptotic effect in cancer cells. Selection of appropriate patients according to the status of TGF-¿ signaling machinery may be critical for future clinical trials to evaluate the therapeutic efficacy of MMP-9 inhibitors. The objective of this research is to define the role of MMP-9 in prostate cancer apoptosis and how the effects of MMP-9 on apoptosis change along with prostate cancer progression. At the completion of this project, we expect to clarify the role of MMP-9 in apoptosis regulation in prostate cancer and how this role may change in relation with the changes of TGF-¿ signaling at different stages of prostate cancer progression.