三萜類天然物熊果酸透過葡萄糖調節蛋白78對人類胃癌細胞之抗癌機制探討

Anticancer effect of ursolic acid, a triterpenoid, on human gastric cancer cells through inhibition of glucose-regulated protein 78

林怡君(Yi-Jiun Lin)

指導教授 ： 黃耀斌

高雄醫學大學/藥學院/藥學系碩士班/碩士(2015年)

摘要

胃癌是台灣高盛行率和高死亡率的癌症。熊果酸(ursolic acid; UA)為一種三萜類天然藥物，過去研究指出具有抗發炎及抗腫瘤的效用，然而UA如何導致胃癌細胞死亡的機制目前仍不清楚。內質網是負責細胞內摺疊蛋白調控，當細胞受到外來刺激，會啟動機制保護細胞。其中內質網壓力相關的輔助摺疊蛋白:葡萄糖調控蛋白78 (glucose-regulated protein 78; GRP78)在胃腫瘤細胞當中過度表現，而促使胃癌細胞的增長，因此抑制GRP78可能可以抑制胃腫瘤細胞的生長。腫瘤相關纖維母細胞被認為和腫瘤的生長及侵襲有關，而腫瘤細胞分泌出的GRP78亦是促使纖維母細胞活化，分化成-smooth muscle actin (-SMA)表現的腫瘤相關纖維母細胞的重要因子。在本研究中發現UA能使人類胃癌細胞走向粒線體相關細胞凋亡，透過抑制GRP78表現，可增加人類胃癌細胞對臨床化療藥物5-fluorouracil (5-FU)的敏感性。UA抑制胃癌細胞GRP78的表現，同時能抑制纖維母細胞的活化。而UA對人類胃癌細胞GRP78的調控，主要透過homeobox protein Hox-A9 (HOXA9)與Yin Yang 1 (YY1)等轉錄因子。除此之外，UA亦透過serine/threonine-protein kinase 1 (PAK1)與降低調控基質金屬蛋白酶的表現，來抑制腫瘤細胞的侵犯和轉移，達到抗癌的效果，因此UA在胃癌的治療上為未來具有潛力的發展藥物。

關鍵字

胃癌 ； 熊果酸 ； 葡萄糖調節蛋白 ； 細胞凋亡 ； 腫瘤微環境

並列摘要

Gastric cancer is a high prevalent and mortality carcinoma in Taiwan. Ursolic acid (UA) is a pentacyclic triterpenoid isolated from Catharanthus trichophyllus roots. It has been reported to process anti-inflammatory and anti-tumor properties. However, the potential role of UA in the mechanism of death of gastric cancer has not been evaluated. Endoplasmic reticulum (ER) stress-related chaperone proteins, GRP78, are overexpressed in gastric cancer tissues, and are important for tumor development and chemotherapy sensitivity. Recently, cancer-associated fibroblasts (CAFs) in cancer microenvironments have been implicated in tumor growth and metastasis of various cancers. GRP78 may link with promoting fibroblasts activation by up-regulation of -SMA expression during tumor development. In this study, UA may promote cancer cell apoptosis and enhance chemosensitivity with combination of 5-fluorouracil (5-FU) by elimination of GRP78 and induction of excessive ER stress in cancer cell. Also, UA inhibits the expression of GRP78, as well as the activation of fibroblasts. Moreover, UA regulates GRP78 in gastric cancer through the transcription factor HOXA9 and YY1. Besides, UA decreases the expression of MMPs to inhibit invasion, and inhibits gastric cancer migration of gastric cancer through PAK1. In conclusions, these results indicate that UA induces gastric cancer cell death and suppresses fibroblasts activation as well as gastric cancer cell migration. UA may be regarded as a promising agent in anti-gastric tumor therapy.

並列關鍵字

gastric cancer ； ursolic acid ； glucose-regulated protein 78 ； apoptosis ； tumor microenvironment

參考文獻

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