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Biological Significance of MCL-1 Upregulation in The Anti-Gastric Cancer Effect of Sulforaphane
|關鍵字:||胃癌;蘿蔔硫素;MCL-1;ERK;NF-κB;抗藥性;Gastric cancer;Sulforaphane;MCL-1;ERK;NF-κB;Drug resistance||引用:||1. Cancer WHO fact sheet. World Health Organization, 2018. http://www.who.int/mediacentre/factsheets/fs297/en/ 2. 105年國人死因統計結果. 衛生福利部. https://www.mohw.gov.tw/cp-16-33598-1.html 3. Gastric Cancer Treatment. National cancer institute. https://www.cancer.gov/types/stomach/patient/stomach-treatment-pdq 4. B. Hu, et al., Gastric cancer: Classification, histology and application of molecular pathology. J Gastrointest Oncol, 2012. 3(3): p. 251-261. 5. P. Lauren, et al., The two histological maintypes of gastric carcinoma: diffuse and so-called instestinal-type carcinoma. An attempt at a histo-clinnical classification. Acta Pathol Microbiol Scand, 1965. 64: p. 31-49. 6. C. Wittekind, et al., The development of the TNM classification of gastric cancer. Pathology international, 2015. 65: p. 399-403 7. M. Orditura, et al., Treatment of gastric cancer. 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胃癌為全球癌症死因排名第四的致命惡性腫瘤；在台灣，胃癌為癌症致死率中排名第七，因此需要更有效的治療。蘿蔔硫素是一種富含在十字花科植物 (如花椰菜和花椰菜嫩芽) 中的異硫氰酸酯 (isothiocyanate)，文獻顯示蘿蔔硫素在不同類型的癌症中具有抗癌、抗發炎和抗氧化作用。本實驗室過去研究指出，蘿蔔硫素透過抑制存活路徑JAK2-STAT3-BCL-2達到抗胃癌效果。有趣的是，我們在胃癌細胞株AGS和MKN45中發現抗凋亡蛋白MCL-1的表現量隨著蘿蔔硫素濃度增加而呈現依賴性上升。先前研究已知MCL-1的上調節在許多癌症中與抗藥性有關。因此，本研究中，我們探討在處理蘿蔔硫素的胃癌中，MCL-1之分子機制與生物意義。我們發現：若將MCL-1 knockdown，可提升蘿蔔硫素對胃癌細胞的細胞毒性，另外，使用UMI-77 (MCL-1抑制劑) 亦可得到相同結果，並明顯增加蘿蔔硫素對胃癌細胞凋亡的誘導，顯示蘿蔔硫素上調節MCL-1表現量引起細胞對自身之抗藥性。此外，我們發現蘿蔔硫素會誘導ERK活化，因此使用U0126 抑制ERK活化，而MCL-1表現量也明顯受到抑制，顯示蘿蔔硫素可能透過ERK活化使MCL-1蛋白穩定性顯著增加。另外一方面，胃癌細胞處理蘿蔔硫素會下調節IκBα表現，並促進p-p65表現，顯示蘿蔔硫素可活化NF-κB活性，而NF-κB為MCL-1之轉錄活化因子。我們使用IκBα super repressor以防止IκBα降解，顯示蘿蔔硫素透過活化NF-κB促使下游MCL-1轉錄活性增加。綜合上述，發現在胃腺癌細胞中，蘿蔔硫素透過活化ERK及NF-κB訊號路徑上調節MCL-1以產生對蘿蔔硫素自身的抗藥性。我們的研究結果為日後蘿蔔硫素合併MCL-1抑制劑做為優化胃癌治療效果之新策略提供理論基礎。
Gastric cancer is the forth most lethal malignancy at present with leading cause of cancer-related death worldwide. In Taiwan, gastric cancer is the seventh leading cause of cancer-related death, thus highlighting the demand for more effective therapeutics. Sulforaphane is a cruciferous vegetables-derived isothiocyanate such as broccoli and broccoli sprouts, which exhibits effective anti-cancer, anti-inflammatory and anti-oxidative actions in various cancers. Our previous research has indicated that the anti-gastric cancer effect of sulforaphane by suppressing the JAK2-STAT3-BCL-2 survival pathway. Interestingly, we found that the level of antiapoptotic MCL-1 was clearly upregulated in sulforaphane-treated gastric cells (AGS and MKN45) in a dose-dependent manner. However, upregulation of MCL-1 has been shown to be associated with drug resistance in various cancers. In this study, we investigated the molecular mechanism and biological significance of MCL-1 in sulforaphane-treated gastric cancer. The cytotoxicity of sulforaphane on gastric cancer cells can be enhanced by knockdown of MCL-1 in gastric cancer cells. Furthermore, the same results were observed with UMI-77 (MCL-1 inhibitor) treatment significantly increase the induction of apoptosis in sulforaphane-treated gastric cancer, suggesting that sulforaphane upregulates MCL-1 to cause its own resistance. In addition, we found that sulforaphane treatment induced ERK activation. We used U0126 to inhibit ERK activation while the expression of MCL-1 is also significantly suppressed, suggesting that sulforaphane treatment led to a marked increase in MCL-1 protein stability, most likely through inducing ERK activation. Furthermore, the level of IκBα was downregulated in sulforaphane-treated gastric cells, indicating that sulforaphane could activate the activity of NF-κB, the transcription factor of MCL-1. We used IκBα super-repressor, which prevents IκBα from degradation, show that sulforaphane treatment promotes the transcriptional activity of MCL-1 by NF-κB activation. In conclusion, upregulation of MCL-1 through ERK and NF-κB pathway are the causes of resistance to sulforaphane in gastric cancer. Our results therefore to provide a new strategy for a better treatment of gastric cancer using sulforaphane in combination with MCL-1 inhibition as a theoretical reference.
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