胰腺導管腺癌（PDAC）是最具侵害性和最致命的腫瘤之一。化學療法是PDAC的主要治療方法，包括gemcitabine (GEM)和cisplatin (CPT)。多數經由GEM或CPT治療的患者其症狀都有明顯改善，但是，少部分的患者卻對其治療產生抗藥性的現象。癌症的抗藥性涉及了多種機制。近年的研究指出，有抗藥性的癌細胞會增加初級纖毛的長度或數量，相反地，抑制初級纖毛生成時會增加癌細胞對化療藥物的敏感性。前人研究也發現在哺乳動物腎細胞和黑色素瘤癌細胞中，異常活化的sterol regulatory element-binding protein-1 (SREBP1)可以抑制初級纖毛的生成。在本篇研究中，我們發現抑制SREBP1活性或是將SREBP1 knockdown後，會促進胰腺導管腺癌PANC-1細胞中初級纖毛的生成。此外，PANC-1細胞在化療藥物GEM和CPT處理後，存活下來的細胞中其生成初級纖毛的比例增加，且細胞中SREBP1 mRNA及蛋白的表達量下降，而纖毛生成相關基因的表達量則增加。另外，在添加GEM的組別中發現乙醯輔酶A羧化酶-1 (acetyl-CoA carboxylase 1, ACC1) 蛋白表現量下降；但在CPT的組別中ACC1蛋白表現則是不變。再經由細胞生長活性測試發現，細胞在處理化療藥物GEM和CPT的情況下，knock down IFT88的細胞存活率確實有明顯的下降，證明了抑制初級纖毛的生成確實可以讓PANC-1細胞對化療藥物GEM和CPT的敏感性增加。因此，根據我們的研究結果顯示，化療藥物GEM和CPT的處理會降低PANC-1細胞中SREBP1的表達量，進而促進初級纖毛的生成，而初級纖毛的生成可以增加PANC-1細胞對GEM和CPT的抗藥性。相反地，抑制初級纖毛的生成可以增加PANC-1細胞對化療藥物GEM和CPT的敏感性。

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly cancers. Chemotherapy is the major therapeutic approach for PDAC, including the usage of gemcitabine (GEM) and cisplatin (CPT). Most cancer cells get killed after GEM or CPT treatment, but a small number of cancer cells display resistance to the treatment. Chemoresistance of cancer cells involves multiple mechanisms; intriguingly, increased number or length of primary cilia have been recently characterized in chemoresistant cancer cells. Nevertheless, inhibition of ciliogenesis enhances chemosensitivity of cancer cells. Previous studies found that aberrant activation of sterol regulatory element-binding protein 1 (SREBP1) inhibited ciliogenesis in mammalian kidney cells and melanoma cancer cells. In this study, we show that inhibition or knockdown of SREBP1 promotes ciliogenesis in PANC-1 cells. In addition, we find that the expression of SREBP1 is decreased and ciliogenesis-related genes are increased after GEM and CPT treatment along with elevated ciliogenesis in PANC-1 cells. Moreover, acetyl-coA carboxylase 1 (ACC1) protein expression is decreased upon GEM treatment but ACC1 protein expression remains unchanged upon CPT treatment. Furthermore, knock down of IFT88 enhances GEM and CPT sensitivities in PANC-1 cells. Therefore, our results indicate that GEM and CPT decrease SREBP1 expression to promote ciliogenesis, which leads to GEM and CPT resistance in PANC-1 cells. On the other hand, inhibition of cilia formation increases chemosensitivity of PANC-1 cells.

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