探討Irisin對前列腺癌細胞的影響

Abstract

前列腺癌是男性癌症中最常見的種類之一，在過去十年，有越來越多的證據指出運動有助於前列腺癌的預防、治療，並提升康復率及生存率，而目前仍不確定運動是如何調節這些效應。近年來，運動誘發的肌肉激素被認為是可能的候選者，鳶尾素 (Irisin) 是在2012年被發現的一種新的肌肉激素，可以促進運動所誘導的白色脂肪細胞棕化。一些研究已經指出，鳶尾素可以抑制不同種癌細胞的進程，然而鳶尾素抑制癌症生長的潛在機制仍未完全瞭解。我們目前的研究揭示，在大腸桿菌系統中表現的人類重組鳶尾素會抑制前列腺癌細胞的遷移和侵襲。鳶尾素會劑量依賴性地抑制癌細胞增殖和群落形成能力，這個現象與誘導細胞凋亡及p21與p27蛋白表現增加導致的G0/G1期細胞週期停滯有關，此外也證明了鳶尾素會開啟前列腺癌細胞的p38絲裂原活化蛋白激酶並抑制細胞外信號調節激酶的訊息傳遞路徑。同時，鳶尾素會促進前列腺癌細胞中的粒線體氧氣消耗並導致過量的氧化壓力。最後，我們發現抗氧化劑N-乙醯半胱氨酸可以反轉癌細胞中鳶尾素所誘導的抗增生作用以及活性氧類的產生。這些發現提供了有關鳶尾素抗癌作用機制的新見解，並支持鳶尾素處理所導致的抗前列腺癌作用與透過調節細胞內的氧化還原平衡有關。

Prostate cancer is one of the most common types of cancer in men. In the past decade, increasing evidence indicated that exercise has benefits in prostate cancer prevention, treatment, recovery, and survivorship. What is not yet clear is how exercise mediates these effects. In recent years, exercise-induced myokines are recognized as potential candidates. Irisin, a myokine discovered in 2012, promotes exercise-induced “browning” of white adipocytes. Several studies have already demonstrated that irisin can inhibit cell progression in various types of cancer. However, the underlying mechanisms of irisin’s inhibitory effects on cancer growth are not yet completely understood. Our present study reveals that recombinant human irisin expressed in the E.coli system inhibited the migration and invasion of prostate cancer cells. Irisin dose-dependently suppressed the proliferation and colony formation ability of cancer cells, associated with the induction of apoptosis and cell cycle arrest at G0/G1 phase with elevated expression of p21 and p27. It also demonstrates that irisin activated the p38 and repressed ERK signaling pathways in prostate cancer cells. Meanwhile, irisin promoted the mitochondrial oxygen consumption as well as the excessive oxidative stress in prostate cancer cells. In the end, we found that the antiproliferative effect and the ROS production induced by irisin in cancer cells can be reversed by NAC, an antioxidant agent. These findings provide the new insight into the mechanism of the anticancer effect of irisin, supporting that irisin-based treatment against prostate cancer is associated with intracellular redox balance modulation.