香菸是導致膀胱癌發生的主要危險因子，並使膀胱癌病人接受化療時產生化療抗性。香菸中的主要成分尼古丁可以在吸煙者的尿液中被偵測出。已有研究指出尼古丁是造成肺癌的一個共同致癌物質，主要是調控促進細胞生長的路徑，並經由抑制細胞凋亡路徑使癌細胞產生化療抗性。但尼古丁造成膀胱癌細胞增生及化療抗性的機轉仍不清楚。本研究主要的目的是探討尼古丁促進膀胱癌細胞生長與化療抗性的分子機轉，並研究紫檀芪對化療敏感性與尼古丁誘發具化療抗性的膀胱癌細胞之治療效果。
我們發現膀胱癌細胞(T24細胞株)短暫暴露尼古丁之後活化Stat3/ERK1/2路徑，增進Stat3及NF-κB與DNA (去氧核醣核酸)結合能力，進而增加cyclin D1蛋白表現以及細胞增生。本研究中具化療抗性的膀胱癌細胞株(Nic-T24 cells, T24R cells)是由持續處理尼古丁的T24細胞建立的。經由長期處理尼古丁，更活化了Stat3路徑而促進cyclin D1過度表現，細胞週期受到干擾使細胞產生化療抗性。我們發現尼古丁促進細胞增生以及化療抗性的主要機制，是透過活化尼古丁受器或β型交感神經受體，造成Stat3及其下游路徑活化。
我們接著發現紫檀芪對化療敏感及尼古丁誘發具化療抗性的膀胱癌細胞具有治療效果。主要是活化細胞壞死、細胞週期停滯、細胞自我吞噬，及細胞凋亡等路徑。紫檀芪能夠藉由抑制AKT/mTOR/p70S6K路徑，以及活化ERK1/2路徑造成細胞自我吞噬作用，合併使用細胞自我吞噬的抑制劑或是針對ERK1/2及Beclin1設計的小髮夾RNA則會促進細胞凋亡產生。
本研究是第一個探討尼古丁促進膀胱癌細胞增生及化療抗性的研究，長期暴露於尼古丁會造成不良的健康效應，包括膀胱癌的發生以及產生化療抗性。本研究也是第一個發現紫檀芪能夠造成癌細胞發生細胞自我吞噬作用，並能夠用來治療化療敏感及尼古丁誘發具化療抗性的膀胱癌。

Cigarette smoke is a major risk factor for bladder cancer and contributes to chemoresistance in bladder cancer patients who continue to smoke while receiving chemotherapy. The main component in cigarette smoke, nicotine, can be detected in the urine of smoker’s. Nicotine has been implicated as a co-carcinogen that promotes lung cancer development through pro-survival pathways and is known to induce chemoresistance in some cancer cells through anti-apoptosis mechanisms. The molecular mechanism of nicotine’s action in bladder cancer cells proliferation and chemoresistance remain unclear. The aims of our study were to investigate the role of nicotine in inducing bladder cancer cells proliferation and chemoresistance, to identify the signaling transduction pathway regulated by nicotine, and further study the anti-cancer effects of pterostilbene in chemosensitive and nicotine-induced chemoresistant bladder cancer cells.
We found that transient nicotine stimulation activates Stat3/ERK1/2 leading to induction of Stat3 and NF-κB DNA binding activity, which is associated with cyclin D1 expression and cell proliferation in bladder cancer cell line T24 cells. Chemoresistant T24 cells (Nic-T24 cells, T24R cells) used in our study were established by persistent nicotine treatment. We provide evidence that chronic nicotine exposure strongly activated Stat3 leading to cyclin D1 overexpression, cell cycle perturbations, and chemoresistance. Nicotine mobilized cell proliferation/chemoresistance is mainly mediated by Stat3 and its downstream signals via nicotinic acetylcholine receptor or β-adrenoceptor.
We further found that pterostilbene effectively inhibits the growth of sensitive and nicotine-induced chemoresistant human bladder cancer cells by inducing necrosis, cell cycle arrest, autophagy and apoptosis. Pterostilbene-induced autophagy was triggered by the inhibition of AKT/mTOR/p70S6K pathway and activation of ERK1/2 pathway. Inhibition of autophagy by pretreatment with autophagy inhibitors or short hairpin RNAs targeting ERK1/2 or Beclin1 enhanced pterostilbene-triggered apoptosis.
This is the first study to investigate signaling effects of nicotine inducing proliferation and chemoresistance in bladder cells. We suggest that people exposed to nicotine could be at risk for potential deleterious effects, including bladder cancer development and chemoresistance. This is also the first study to demonstrate that pterostilbene causes autophagy in cancer cells and suggests that pterostilbene could serve as a new and promising agent for the treatment of sensitive and nicotine-induced chemoresistant bladder cancer cells.

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