ZAK選擇性剪接異構物在腫瘤細胞轉型中的角色

Leucine zipper and sterile alpha motif kinase (ZAK) 是MAPK訊息路徑的調控樞紐之一，參與許多腫瘤發生相關的調控，如細胞轉型、增生及運動性等。zak基因透過選擇性剪接 (Alternative splicing) 產生ZAKα及ZAKβ兩個轉錄異構體。我們發現ZAKα在腫瘤組織中的蛋白質表現量相對高於其鄰近正常組織；ZAKβ則相反。ZAKα及/或其激酶活性會調控癌細胞非貼附型生長及抑制cAMP訊息路徑；而ZAKβ蛋白質在癌細胞中異位表現會抑制癌細胞增生及其非貼附型生長。ZAKα及ZAKβ蛋白質表現比例可能在cAMP訊息路徑的調節中扮演重要角色；且ZAKβ或CREB 1在癌細胞中大量表現時，會抑制癌細胞非貼附型生長及減少Cox2及β-catenin蛋白質表現，根據這些結果推論ZAKβ及CREB 1都是具有抗癌特性的分子。另外，我們發現Doxorubicin會改變癌細胞內ZAKα及ZAKβ的蛋白質表現比例，並造成癌細胞無法在soft agar中生長，這說明了如何利用藥物重新改編細胞內的基因剪接調控來改變細胞內蛋白質的表現，進而啟動內源性的抗癌特性。有鑒於ZAKα為癌症生長所必須，因此我們選用許多研究證實可以抑制許多種癌細胞生長並誘發細胞程序性凋亡的常用天然營養化合物--薑黃素，來進一步檢測ZAKα的功能。探討是否能利用薑黃素來壓制ZAKα所誘發的細胞增生以及薑黃素的抑癌分子機轉。我們發現薑黃素會藉由減弱ZAKα的激酶活性來改變細胞週期的調控及促進細胞凋亡。

Leucine zipper and sterile alpha motif kinase (ZAK) participates in MAPK signaling pathway and relates to the control of oncogenesis, including cell transformation, proliferation and motility. ZAK exists two alternative isoforms, ZAKα and ZAKβ. We found that ZAKα proteins were up-regulated in tumor tissues relative to its adjacent normal one where ZAKβ proteins were relativly abundant. ZAKα might regulate anchorage-independent growth in cancer cells and suppress cAMP signaling pathway in a kinase-dependent manner. Overexpression of ZAKβ protein declined cancer cell proliferation. Therefore, we pronounced that the protein expression ratio of ZAKα and ZAKβ might be a key regulator of cancer cell proliferation. Besides, overexpression of ZAKβ or CREB 1, a downstream molecule of cAMP signaling pathway, in cancer cells suppressed anchorage independent growth and also decreased Cox2 and β-catenin proteins, suggesting that both ZAKβ and CREB 1 were potent antitumor molecules. Induction of endogenous ZAKβ by doxorubicin leads to cancer cells failed to grow in soft agar demonstrating how pharmacological manipulates endogenous reprogramming splicing event could manifest powerful antitumorigenic properties. Curcumin is one of the popular nutritional compounds for its anticancer effects. Here, we investigate if curcumin could suppress ZAKα-induced cancer cell proliferation and uncover the molecular mechanisms in curcumin-induced anticancer effects. Our data revealed that inactivation of ZAKα activity is a novel mechanism of action for curcumin mediated anticancer activity.