探討AXL受體酪胺酸激酶參與科羅索酸抑制人類膠質母細胞瘤轉移之分子機轉

人類膠質母細胞瘤 (glioblastoma) 是腦癌中常見的一種惡性腫瘤，現有的治療方式成效不彰，且由於膠質母細胞瘤具有高度侵入性，因此預後大多不佳。近年來也有研究指出中草藥活性成分對某些癌症細胞具有毒殺效果，我們也期望能從中發展出治療膠質母細胞瘤的有效藥物。科羅索酸 (Corosolic acid; CA) 是一種從獼猴桃中提取的生物活性化合物，過去研究指出科羅索酸具有抗發炎、抗氧化、抗癌以及抗轉移等多重生物功能，然而科羅索酸是否對膠質母細胞瘤細胞具有抗癌活性仍不清楚。我們的研究證實科羅索酸不影響正常星形膠質細胞和四種膠質母細胞瘤的細胞生長和細胞增殖率。值得注意的是，科羅索酸顯著抑制膠質母細胞瘤細胞的移動和侵襲能力，並且降低F-肌動蛋白(F-actin)蛋白質表現及聚合能力。進一步的研究證實，科羅索酸顯著抑制AXL酪胺酸激酶受體(AXL)蛋白表現，但不影響AXL mRNA表現。此種現象是科羅索酸促進熱休克蛋白70羧基端相互作用蛋白(CHIP)表現增加進而降解 AXL 蛋白表現。此外我們也發現抑制CHIP 會減少科羅索酸抑制AXL蛋白表現及膠質母細胞瘤細胞的侵襲能力。此外，我們也觀察到科羅索酸抑制生長終止特異性蛋白6 (GAS6)和 JAK2/MEK/ERK 活化路徑，過度表現 GAS6 會減弱科羅索酸抑制JAK2/MEK/ERK 活化路徑和膠質母細胞瘤細胞的侵襲能力。利用分子對接軟體分析說明科羅索酸可能與 GAS6 和 AXL 相互結合。以上這些研究說明科羅索酸抑制膠質母細胞瘤細胞的轉移能力是透過誘導CHIP蛋白表現來降解AXL蛋白，進而抑制GAS6 調控JAK2/MEK/ERK 訊傳遞路徑。總之，本研究證實科羅索酸對膠質母細胞瘤細胞具有潛在的抗轉移活性。

關鍵字

膠質母細胞瘤；科羅索酸；細胞移動；細胞侵襲； AXL酪胺酸激酶受體； F-肌動蛋白；生長終止特異性蛋白6 ；熱休克蛋白70羧基端相互作用蛋白

並列摘要

Humna glioblastoma (GBM) is a common malignancy in brain cancer and is highly invasion, lead to current treatment are low effective and high mortality rate, lead to the poor prognosis of GBM patient. Recent years, large of studies have been suggest that activate compounds of chinese herbal medicine is cytotoxic effects on certain tumor cells. We also expect to develop potential effective anticancer drugs against GBM. Corosolic acid (CA), a bioactive compound obtained from Actinidia chinensis, has potential anti-inflammation, anti-oxidation, anti-cancer and anti-metastasis abilities against various types of tumor cells. This study was aimed to explore the anticancer activity and its underlying mechanism of CA in GBM cells. Our findings showed that CA did not affect cell viability and cell proliferative rate of normal astrocyte and GBM cells. Notably, CA significantly inhibited cell migration and invasion of GBM cells, decreased the protein level of F-actin and disrupted F-actin polymerization in these GBM cells. Further investigation revealed that CA decreased the protein level of AXL, not mRNA level of AXL. CA inhibited AXL level by promoting ubiquitin-mediated proteasome degradation and upregulating the CHIP, an inducer of AXL polyubiquitination. CHIP knock-down restored the CA-reduced AXL and inva-siveness of GBM cells. Additionally, we observed that CA-reduced Growth arrest-specific protein 6 (GAS6) and inhibited JAK2/MEK/ERK activation, and GAS6 pre-treatment restored attenuated JAK2/MEK/ERK activation and invasiveness of GBM cells. Furthermore, molecular docking anal-ysis revealed that CA might bind to GAS6 and AXL. These findings collectively indicate that CA attenuates the invasiveness of GBM cells, attributing to CHIP upregulation and binding to AXL, subsequently promoting AXL degradation and downregulating GAS6-mediated JAK2/MEK/ERK cascade. Conclusively, this suggests that CA has potential anti-metastatic activity on GBM cells.

並列關鍵字

Glioblastoma ； Corosolic acid ； Cell migration ； Cell invasion ； AXL ； F-actin ； GAS6 ； CHIP

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