探討阿斯匹靈合併曲格列酮協同性抑制非小細胞肺癌細胞株A549的移動和侵犯能力

肺癌是全世界癌症疾病中死亡率最高的一種，其中肺癌的死因主要是癌細胞轉移的發生。在我們先前的研究中發現Troglitazone (TGZ)，一種脂肪分化轉錄因子的核內受體(Peroxisome proliferator-activated receptor γ; PPARγ)的致效劑合併阿斯匹靈(Aspirin; ASA;非選擇性COX-1和COX-2抑制劑)處理癌細胞會有強烈的加成作用，具有使肺癌細胞的細胞週期停滯和誘導細胞凋亡而達到抗癌的效果。然而，合併ASA和TGZ對於癌細胞的轉移是否有影響還沒有深入的探討。因此，我們針對ASA合併TGZ是否能夠影響肺癌細胞爬行(migration)和侵犯(invasion)及其相關機制做了更深入的探討。在傷口癒合分析(wound healing assay)和轉移盤爬行分析(transwell migration assay)中，我們發現了ASA合併TGZ比起單獨ASA或TGZ處理A549細胞株，具有更強烈的抑制細胞爬行的效果。相似的結果在轉移盤侵犯分析(transwell invasion assay)中也發現，合併ASA和TGZ處理細胞之後具有強烈抑制細胞侵犯能力的效果。我們也發現了ASA合併TGZ抑制細胞爬行的加成效果是源於PPARγ活化和COX-1、COX-2的部分參與。我們更進一步的發現到兩種藥物合併之後，會透過抑制FAK(focal adhesion kinase)和Axl(一種酪胺酸激酶受體;Receptor tyrosine kinase)的訊息傳遞影響使細胞的爬行和侵犯能力受到抑制。因此，我們的研究結果提供了新的見解，並且說明了ASA合併TGZ組合治療腫瘤細胞轉移的相關機制，並且也可能提供一個治療肺癌新的治療方式。

關鍵字

阿斯匹靈；曲格列酮；移動；侵犯； FAK ； AXL

並列摘要

Lung cancer is the leading cause of cancer-related deaths worldwide and the majority of deaths in lung cancer are caused by metastasis. Our previous studies demonstrated that Troglitzone (TGZ), a peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist, combined with Asprin (ASA), a nonselective cyclooxygenase (COX) inhibitor, had synergistic anticancer effects through cell cycle arrest and apoptosis in lung cancer cells. However, the effect of combination treatment with TGZ and ASA on cancer cell metastasis has not been investigated. Thus, we continued to investigate whether the combination treatment of TGZ and ASA affects lung cancer cells migration, and invasion and to study its underlying mechanism. In wound healing assay and transwell migration assay, cell mobility was markedly suppressed by combined ASA and TGZ compared with individual treatment in A549 cells. Similar results in transewll invasion assay were obtained, the combination treatment notably inhibited cells invasion. We also found that combination treatment of ASA and TGZ suppressed migration and invasion via inhibition of FAK and Axl signaling pathways and the synergistic effect may involve PPARγ, and partially COX-1 and COX-2 dependent. My study may provide new insights into the possible mechanisms underlying the TGZ and ASA combination treatment in cancer cells migration, and may potentially provide a therapeutic strategy for lung cancer treatment.

並列關鍵字

Aspirin ； Troglitazone ； Migration ； Invasion ； FAK ； AXL

參考文獻

Abdin AA, Baalash AA, Hamooda HE (2010). Effects of rosiglitazone and aspirin on experimental model of induced type 2 diabetes in rats: focus on insulin resistance and inflammatory markers. J Diabetes Complications 24: 168–178.

Allred CD, Kilgore MW (2005). Selective activation of PPARgamma in breast, colon, and lung cancer cell lines. Mol Cell Endocrinol 235: 21-29.

Arenberg VGKRCRDA, Joel B, Thannickal VJ, Kalemkerian GP, Standiford TJ (2004). Peroxisome proliferator-activated receptor-gamma activation inhibits tumor progression in non-small-cell lung cancer. Oncogene 23: 100-108.

Borthwick GM, Johnson AS, Partington M, Burn J, Wilson R, Arthur HM (2006). Therapeutic levels of aspirin and salicylate directly inhibit a model of angiogenesis through a Cox-independent mechanism. FASEB J 20: 2009-2016.

Bren-Mattison Y, Van Putten V, Chan D, Winn R, Geraci MW, Nemenoff RA (2005). Peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC). Oncogene 24: 1412-1422.

國際替代計量

探討阿斯匹靈合併曲格列酮協同性抑制非小細胞肺癌細胞株A549的移動和侵犯能力

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