摘要: | 前列腺癌在美國是男性最常被診斷出的癌症,並具有高度轉移至其他器官的能力及特性。緩激?(Bradykinin,BK)是一個炎症的介質。在損傷嚴重之部位和在發炎性疾病時會明顯地升高,最近BK已被證實與致癌和癌症的進展相關。然而,緩激?對於人類前列腺癌細胞株轉移能力的影響目前仍不清楚。在我們的實驗中發現,緩激?能增加人類前列腺癌細胞株 (PC3、DU145及LNCaP) 的轉移能力以及腫瘤細胞上matrix metalloproteinase (MMP)-9和intercellular adhesion molecule-1 (ICAM-1)的表現。當我們給予前列腺癌細胞緩激?B2 接受器拮抗劑則會降低緩激?所誘導的細胞轉移能力或MMP-9和ICAM-1的表現。前列腺癌細胞被緩激?刺激後即能偵測到Protein kinase C delta (PKCδ)、c-Src及nuclear factor kappa B (NF-κB)訊號傳遞路徑活化的表現;此外緩激?所誘導的細胞轉移能力或MMP-9的表現也會被PKCδ、c-Src及NF-κB的抑制劑所抑制,由實驗結果得知緩激?能藉由B2 receptor、PKCδ、c-Src及NF-κB的訊號傳遞路徑,造成前列腺癌細胞的轉移且造成MMP-9的表現增加。當我們更進一步地研究ICAM-1在緩激?調節前列腺癌細胞轉移能力中扮演的角色時,實驗結果顯示緩激?的確能增加人類前列腺癌細胞株(PC3、DU145及LNCaP) ICAM-1的表現。當我們給予前列腺癌細胞緩激?B2 receptor、phosphatidylinositol 3-kinase (PI3K)、Akt及activator protein-1 (AP-1)抑制劑或將其dominant-negative mutant轉殖入PC3細胞株後,皆會降低緩激?對於細胞株轉移能力的影響及ICAM-1的表現。從此結果來看,我們發現緩激?也能藉由B2 receptor、PI3K、AKT及AP-1的訊號傳遞路徑,造成造成前列腺癌細胞的轉移且ICAM-1的表現增加。總而言之,以上的結果或許對於前列腺癌細胞轉移的機制有更進一步地了解,並希望對於制定相關的治療策略有所幫助。
Prostate cancer is the most commonly diagnosed malignancy in men in USA. Prostate cancer shows a predilection for metastasis to the distant organs. Bradykinin (BK) is an inflammatory mediator, and shows elevated levels in regions of severe injury and inflammatory diseases. Recently BK has been shown to be involved in carcinogenesis and cancer progression. However, the effect of BK on migration activity in human prostate cancer cells is mostly unknown. Here we found that BK increased the migration and expression of matrix metalloproteinase (MMP)-9 and adhesion molecule intercellular adhesion molecule-1 (ICAM-1) in human prostate cancer cells. B2 receptor inhibitor or small interfering RNA (siRNA) reduced BK-mediated cell migration and MMP-9 expression. In addition, BK-mediated migration and MMP-9 up-regulation were attenuated by Protein kinase C delta (PKCδ), c-Src, and Nuclear factor kappa B (NF-κB) inhibitor. Activation of the PKCδ, c-Src, and NF-κB signaling pathway after BK treatment was demonstrated, and BK-induced expression of MMP-9 and migration activity were inhibited by the specific inhibitor, and mutant of PKCδ, c-Src, and NF-κB cascades. Those results indicated that BK enhances the migration of prostate cancer cells by increasing MMP-9 expression through the B2 receptor, PKCδ, c-Src, and NF-κB signal transduction pathway. The adhesion molecule ICAM-1 also plays a critical role during tumor metastasis. Furthermore, stimulation of prostate cancer cells with BK induced mRNA and protein expression of ICAM-1. Pretreatment of prostate cancer cells with B2 receptor, phosphatidylinositol 3-kinase (PI3K), Akt, and activator protein-1 (AP-1) inhibitors or mutants abolished BK-promoted migration and ICAM-1 expression. Our results indicate that BK enhances the migration of prostate cancer cells by increasing ICAM-1 expression through a signal transduction pathway that involves the B2 receptor, PI3K, Akt, and AP-1. Thus, BK represents a promising new target for treating prostate cancer metastasis. |