Hispolon誘發人類子宮頸癌細胞自體吞噬與抑制腫瘤轉移之機制探討

The Mechanisms of Hispolon in Autophagy Induction and Metastasis Inhibition in Human Cervical Cancer Cells

辛旻潔(Min-Chieh Hsin)

指導教授 ： 楊順發

中山醫學大學/醫學院/醫學研究所/博士(2018年)

摘要

Hispolon為桑黃分離出來的酚類化合物，已知可誘導癌細胞的凋亡與抗腫瘤作用。然而，在子宮頸癌中對於腫瘤的活性抑制以及所涉及之分子機制，至今還未有深入的探討。在本篇實驗中，我們發現Hispolon治療能抑制兩株子宮頸癌細胞的細胞轉移。在體外與體內實驗中，溶酶體組織蛋白酶S (Cathepsin S, CTSS)的下調對其腫瘤細胞轉移的抑制至關重要。此外，Hispolon誘發子宮頸癌細胞產生細胞自體吞噬，其增加LC3轉化和酸性囊泡胞器的形成。在機制方面，我們發現Hispolon透過細胞外訊號調節激酶 (Extracellular signal-regulated kinase, ERK)途徑抑制子宮頸細胞其細胞的移動能力，而阻斷ERK途徑則逆轉細胞自體吞噬所調節的細胞轉移與CTSS 的抑制。我們的研究結果表明，Hispolon所誘發的細胞自體吞噬對於降低CTSS活性來抑制子宮頸癌腫瘤轉移是至關重要的；這一發現為分子調控提供了新的視角。

關鍵字

子宮頸癌 ； Hispolon ； 細胞自體吞噬 ； 半胱氨酸組織蛋白酶癌症轉移

並列摘要

Hispolon, a phenolic compound isolated from Phellinus igniarius, induces apoptosis and anti-tumor effects in cancers. However, the molecular mechanism involved in hispolon-mediated tumor-suppressing activities observed in cervical cancer is poorly characterized. Here, we demonstrated that treatment with hispolon inhibited cell metastasis in two cervical cancer cell lines. In addition, the downregulation of the lysosomal protease Cathepsin S (CTSS) was critical for hispolon-mediated suppression of tumor cell metastasis in both in vitro and in vivo models. Moreover, hispolon induced autophagy, which increased LC3 conversion and acidic vesicular organelle formation. Mechanistically, hispolon inhibited the cell motility of cervical cells through the extracellular signal regulated kinase (ERK) pathway, and blocking of the ERK pathway reversed autophagy-mediated cell motility and CTSS inhibition. Our results indicate that autophagy is essential for decreasing CTSS activity to inhibit tumor metastasis by hispolon treatment in cervical cancer; this finding provides a new perspective on molecular regulation.

並列關鍵字

Cervical cancer ； Hispolon ； Autophagy ； Cysteine Cathepsins ； Metastasis

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