三萜類抗癌化合物樺木酸誘導人類胃癌細胞內質網壓力與調控腫瘤微環境機制之探討

胃癌是台灣盛行並造成高致死率的癌症。而樺木酸(Betulinic acid；BA)為一種萃取自白樺樹的三萜類天然物，並被認為具有抗發炎以及抗腫瘤的功效，然而BA如何誘導胃癌細胞死亡的機制目前仍不清楚。內質網是細胞內負責轉譯、摺疊分泌蛋白與鈣離子調控的胞器，因此內質網的衡定對於外來擾動相當敏感，當細胞受到刺激時會啟動適應機制來保護細胞。這些外在刺激包括細胞內鈣離子調控失去平衡，氧化壓力與過多未摺疊蛋白的堆積。過去研究顯示內質網壓力相關的輔助折疊蛋白在許多的癌組織中被過度表現，這可能與腫瘤的形成息息相關。因此抑制促進生存的輔助折疊蛋白，並且導入內質網壓力應可促進癌細胞死亡。近來腫瘤相關纖維母細胞在腫瘤微環境中被認為會促進腫瘤生長與侵襲。TGF-?珧T息傳遞在腫瘤的形成中更可能扮演著經由??-SMA表現上升來促使纖維母細胞活化。根據此論點，本研究中發現BA會透過抑制人類胃癌細胞MKN45與CS12內質網壓力相關的促進生存輔助蛋白，並活化內質網壓力-粒線體相關細胞凋亡路徑。BA不但可促使胃癌細胞死亡，並且可能透過HOXA9，來抑制胃癌細胞TGF-?猁漯穛{，進而抑制人類纖維母細胞HS68的活化。因此本研究提供了BA促進胃癌細胞死亡與抑制纖維母細胞活化的分子機制，BA也許可成為未來胃癌治療的有效藥劑。

關鍵字

樺木酸；胃癌；細胞凋亡；腫瘤微環境

並列摘要

Gastric cancer is a high prevalent carcinoma and the leading cause of cancer-related mortality in Taiwan. Betulinic acid (BA), a triterpene isolated from the white birch tree, has been reported to exhibit anti-inflammatory and anti-tumor properties. However, the mechanisms of BA responsible for the induction of gastric cancer death remain unclear. The endoplasmic reticulum (ER) is a membranous network within cells, and it is important for several cellular functions, including translation, folding of secretory proteins and sequestration of Ca2+. ER homeostasis is very sensitive to perturbations in cellular homeostasis and activates an adaptive response when it senses stressful conditions. This can occur in response to conditions such as, disturbed Ca2+ homeostasis, accumulation of misfolded proteins and oxidative stress. Numerous studies have also shown that ER stress-related chaperone proteins are overexpressed in many cancers, and are important for tumor development. Therefore, elimination of pro-survival chaperone proteins and induction of excessive ER stress may promote cancer cell apoptosis. Recently, cancer-associated fibroblasts (CAFs) in cancer microenvironments have been implicated in tumor growth and metastasis of various cancers. TGF-?? signaling may link with promoting fibroblast activation by up-regulation of ??-SMA expression during tumor development. In this regard, the present study assessed the anticancer effects of BA on human gastric cancer cells. A mechanistic analysis demonstrated that BA-induced human gastric cancer cell death was down-regulation of ER stress-related pro-survival chaperones and activation of mitochondrial-dependent apoptosis pathway. BA not only induced gastric cancer cell death, attenuated TGF-?? expression partially through HOXA9-mediated pathway, but also inhibited TGF-??-induced human fibroblasts (HS68) activation. In conclusions, these results provide a molecular basis for the ability of BA to mediate gastric cancer death, suppress fibroblasts activation. BA may be regarded as a promising agent in anti-gastric tumor therapy.

並列關鍵字

Betulinic acid ； gastric cancer ； apoptosis ； tumor microenvironment

參考文獻

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三萜類抗癌化合物樺木酸誘導人類胃癌細胞內質網壓力與調控腫瘤微環境機制之探討

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