Cystathionine gamma-lyase在前列腺癌轉移中的角色

Abstract

在男性中前列腺癌的發生率列居前位，並且死亡率也位居第二高。前列腺癌早期通常生長緩慢而且沒有任何症狀，一旦病人發現症狀就醫，癌細胞經常已經轉移到身體其他部位，尤其以骨骼最為常見。有骨轉移時會引起骨骼疼痛，甚至造成死亡，因此研究前列腺癌的轉移機制以找出可做為潛力藥物為本研究之主要目標。此研究為探討代謝酵素¬¬–cystathionine gamma-lyase (CTH)在前列腺癌中所扮演的角色。比較前列腺原位癌細胞和骨轉移癌細胞後發現，CTH在骨轉移的癌細胞中的表現量遠高於原位癌細胞，而且具有促進細胞移動、入侵、血管新生等能力。CTH在催化胺基酸代謝時會產生硫化氫（H２S），而此氣體已經被發現為一種氣體傳導物質。H２S可以透過對蛋白質硫基化修飾來調控NF-κB的蛋白活性。此外，CTH也會促進IL-1β在細胞中的表現量，進而誘導NF-κB磷酸化並入核改變下游基因之表達。數據證實CTH可藉由H２S和IL-1β提升癌細胞入侵的能力和促進內皮產生血管新生，因此推測前列腺癌所表現的CTH可以調控H２S和IL-1β進而活化NF-κB路徑，因而促使癌細胞之轉移。

Prostate cancer is one of the most common cancers and the second leading cause of death from cancer in men. Metastatic prostate cancer most commonly spreads to the bones and lymph nodes. Bone metastasis is painful and has no cure. Thus, the main goal of this study is to identify potential drug targets in treating prostate cancer bone metastasis. In this study, the role of a metabolic enzyme, cystathionine gamma-lyase (CTH), was investigated. We found that CTH was up-regulated in bone-metastatic prostate cancer cells, and it positively regulated cell migration, cell invasion and angiogenesis. CTH enhanced expression of IL-1β, resulting in increased phosphorylation of p65 subunit of NF-κB. p65 nuclear translocation was promoted by CTH through H2S and/or IL-1β. Treatment of H2S or IL-1β increased cell invasion and angiogenesis. Collectively, our data suggests that CTH likely plays an important role in promoting prostate cancer cell invasion and metastasis through production of H2S and IL-1β.