初級纖毛是由微管組成的一種非運動性的胞器，從基體延伸至細胞表面，在感知和細胞內信號傳導中發揮關鍵作用。在胰腺導管腺癌（PDAC）中，初級纖毛的丟失是一種常見現象，但有研究發現，在順鉑治療後的 PDAC 與順鉑抗藥性的 PDAC 皆有發現初級纖毛再生的現象，暗示初級纖毛可能有參與順鉑化療抗藥的機制。然而，癌細胞經常重新編程其脂質代謝以滿足快速生長和增殖的條件需求，抑或適應不良環境，有研究指出由初級纖毛介導的 Hedgehog 訊號通路會抑制脂質重頭生成路徑，另外，我們先前的研究得知麩醯胺酸合成酶（GS）和脂質代謝有關，但在 PDAC 中初級纖毛、GS 與脂質代謝改變相關的調控機制及其在順鉑化療敏感性中的連結仍不清楚。在本研究結果顯示，在經順鉑處理的 PANC-1 細胞和順鉑抗藥性的 CPTR（Cisplatin resistance） PANC-1 中，GS、初級纖毛相關的蛋白內纖毛轉運蛋白 88（IFT88）以及分化簇 36（CD36）的蛋白和基因表現量表達皆增加，並伴隨著脂肪酸攝取的增強，並且在 PANC-1 抑制 GS 表達可降低經順鉑處理後細胞的纖毛生成、CD36 表達和脂肪酸攝取，在 CPTR PANC-1 中也有相同現象。同樣地，在 PANC-1 和 CPTR PANC-1 中抑制 IFT88 也導致 CD36 表達和脂肪酸攝取的減少。此外，敲低 GS、IFT88 和 CD36 可降低 PANC-1 和 CPTR PANC-1 細胞對順鉑的半數抑制濃度（IC50），增強細胞對順鉑的敏感性。研究結果顯示，GS 促進初級纖毛的形成，進而上調CD36的表達並增強脂肪酸攝取，從而降低 PANC-1 對順鉑的敏感度，減少順鉑對 PANC-1 的治療效果。本研究提供了 GS 在調控初級纖毛、脂質代謝及 PDAC 順鉑化療抗藥中的作用的初步見解，並提出其作為潛在治療靶點的可能性。

Primary cilia, non-motile organelles composed of microtubules that extend from the basal body to the cell surface, play a critical role in sensory perception and intracellular signaling. In pancreatic ductal adenocarcinoma (PDAC), the loss of primary cilia is a common phenomenon. However, studies have observed the regeneration of primary cilia in both cisplatin-treated PDAC and cisplatin-resistant PDAC, suggesting that primary cilia may be involved in the mechanisms of cisplatin resistance. Cancer cells frequently reprogram their lipid metabolism to meet the demands of rapid growth and proliferation or adapt to adverse environmental conditions. Notably, the primary cilia-mediated Hedgehog signaling pathway has been reported to suppress the de novo lipogenesis pathway. Our previous findings revealed that glutamine synthetase (GS) is associated with lipid metabolism, but the regulatory mechanisms linking primary cilia, GS, and altered lipid metabolism to cisplatin sensitivity in PDAC remain unclear.In this study, we demonstrated that both cisplatin-treated PANC-1 cells and cisplatin-resistant CPTR PANC-1 cells exhibited increased protein and gene expression levels of GS, the primary cilia-associated protein intraflagellar transport protein 88 (IFT88), and cluster of differentiation 36 (CD36), accompanied by enhanced fatty acid uptake. Knockdown of GS in PANC-1 cells reduced ciliogenesis, CD36 expression, and fatty acid uptake following cisplatin treatment, and the same phenomenon was observed in CPTR PANC-1 cells. Similarly, knockdown of IFT88 in both PANC-1 and CPTR PANC-1 cells led to a decrease in CD36 expression and fatty acid uptake. Furthermore, knockdown of GS, IFT88, and CD36 reduced the half-maximal inhibitory concentration (IC50) of cisplatin in both PANC-1 and CPTR PANC-1 cells, thereby enhancing cisplatin sensitivity.These findings suggest that GS promotes the formation of primary cilia, which subsequently upregulates CD36 expression and enhances fatty acid uptake, thereby reducing the cytotoxic effects of cisplatin. This study provides preliminary insights into the role of GS in regulating primary cilia, lipid metabolism, and cisplatin resistance in PDAC, highlighting its potential as a therapeutic target.

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