LL-37 as a therapeutic target for late stage prostate cancer.
LL-37 as a therapeutic target for late stage prostate cancer.
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DOI：
10.1002/pros.21282
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发表时间：
2011-05
期刊：
影响因子：
2.8
通讯作者：
Ponnazhagan, Selvarangan
中科院分区：
文献类型：
--
作者：
Hensel, Jonathan A.;Chanda, Diptiman;Kumar, Sanjay;Sawant, Anandi;Grizzle, William E.;Siegal, Gene P.;Ponnazhagan, Selvarangan
抗菌肽LL-37(亮氨酸-亮氨酸-37)刺激细胞增殖、血管生成和细胞迁移，抑制细胞凋亡，并与炎症有关。由于这些功能过程在癌症中经常被夸大，本研究的目的是研究IL-37在前列腺癌(PCa)中的表达和作用，并建立其作为治疗靶点的价值。我们分别检测了IL-37及其同源基因长春新碱相关抗菌肽(CRAMP)在人和小鼠前列腺肿瘤中的表达。与正常/良性前列腺组织相比，随着前列腺癌及其转移程度的增加，人前列腺癌组织和转基因小鼠前列腺癌(TRAMP)模型中IL-37和JRAMP均呈高表达。随后，我们通过RNA干扰(RNAi)策略在高致瘤性的TRAMP-C1细胞系中抑制了JRAMP，以检测JRAMP在细胞增殖、血管生成、侵袭、凋亡、信号通路激活和肿瘤动力学中的重要性。在体外，JRAMP的表达降低了细胞的增殖、侵袭力、IV型胶原酶、磷酸化ERK1/2和Akt信号转导的量。这些结果在活体内是平行的。同种异体移植的TRAMP-C1细胞经痉挛敲除后，肿瘤发生率和肿瘤大小减少，促肿瘤机制下调。在小鼠前列腺癌模型中的抽筋敲除类似地展示了LL-37在前列腺癌中的致癌作用，以及它作为治疗前列腺癌和潜在的其他过度表达多肽的癌症的新的治疗靶点的潜力。
The antimicrobial peptide, LL-37 (leucine-leucine-37), stimulates proliferation, angiogenesis and cellular migration, inhibits apoptosis and is associated with inflammation. Since these functional processes are often exaggerated in cancer, the aim of the present study was to investigate the expression and role of LL-37 in prostate cancer (PCa) and establish its value as a therapeutic target. We evaluated the expression of LL-37 and the murine orthologue, Cathelicidin Related Anti-Microbial Peptide (CRAMP) in human and murine prostate tumors, respectively. Compared to normal/benign prostate tissue, both LL-37 and CRAMP were increasingly over-expressed with advancing grades of primary prostate cancer and its metastasis in human tissues and in the Transgenic Adenocarcinoma Mouse Prostate (TRAMP) model, correspondingly. We subsequently knocked down CRAMP in the highly tumorigenic TRAMP-C1 cell line via a RNA interference (RNAi) strategy to examine the importance of CRAMP on cellular proliferation, angiogenesis, invasion, apoptosis, activation of signaling pathways and tumor kinetics. Abrogation of CRAMP expression led to decreased proliferation, invasion, type IV collagenase, and the amount of phosphorylated Erk1/2 and Akt signaling in vitro. These results were paralleled in vivo. Syngenic implantation of TRAMP-C1 cells subjected to CRAMP knock-down resulted in a decreased tumor incidence and size, and the down regulation of pro-tumorigenic mechanisms. CRAMP knockdown in a murine prostate cancer model analogously demonstrated the tumorigenic contributions of LL-37 in PCa and its potential as a novel therapeutic target for the treatment of PCa and potentially, other cancers over-expressing the peptide.
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