卵巢癌是世上最致命的婦科惡性癌症之一。大多數婦女確診時已為晚期，而在給予手術和化學治療後常會復發，且復發的卵巢癌常伴隨著抗藥性。因此，找尋新的方法及組合來治療抗藥性的卵巢癌是迫切需要。來自哺乳類細胞以及植物之天然產物的內生性大麻素以及大麻素已被證明在不同腫瘤中具有抗腫瘤的潛力。然而，很少有研究探討內生性大麻素在卵巢癌中的作用機制。本研究提出了以下假設：內生性大麻素通過神經醯胺誘導的內質網壓力來抑制具抗藥性的卵巢癌的細胞活性。藉由細胞活性測試，發現隨著濃度的增加，內生性大麻素(AEA和2-AG)降低了卵巢癌細胞株（IGROV1和ES2）的細胞活性。藉由西方墨點法，我們發現內生性大麻素引起抗藥性卵巢癌明顯的內質網壓力並且活化了三個未摺疊蛋白反應途徑，最後增加了內質網引起細胞凋亡途徑中的關鍵蛋白CHOP的表現量。結合內生性大麻素的治療，可以讓抗藥性的卵巢癌細胞對於化療試劑之毒殺作用更為敏感。在免疫螢光染色的實驗，我們發現內生性大麻素所誘導的內質網壓力，伴隨著細胞中神經醯胺的累積。藉由抑制劑的實驗，我們發現內生性大麻素所引起的內質網壓力是透過增加細胞中神經醯胺的生合成。綜合本研究所有的實驗，利用內生性大麻素引起神經醯胺的累積以及過量的內質網壓力，可能為治療卵巢癌一種有效的選擇。

Ovarian cancer is one of the most lethal gynecological malignancies worldwide. Most women present with late-stage disease, and develop recurrence after surgery and chemotherapy. Besides, almost all patients relapse with chemoresistant disease. Therefore, new approaches to treat chemoresistant ovarian cancer are urgently needed. (Endo)cannabinoids, natural products from mammalian cells and plants, have been demonstrated to have promising potential as antitumor agents in different types of tumors. However, few studies have investigated the mechanism of action of endocannabinoids in the treatment of ovarian cancer. This study addressed the hypothesis that endocannabinoids inhibit cell viability of chemoresistant ovarian cancer cells through ceramide-induced endoplasmic reticulum (ER) stress. We found that the endocannabinoids N-arachidonoylethanolamine and 2-arachidonoylglycerol (AEA and 2-AG, respectively) decreased ovarian cancer cells (IGROV1 and ES2) viability in a dose-dependent manner. We further demonstrated that endocannabinoids elicited pronounced ER stress, activated unfolded protein response (UPR) pathways, and increased C/EBP homologous protein (CHOP) levels in ovarian cancer cells. Reportedly, combination therapy with endocannabinoids sensitizes chemoresistant ovarian cancer cells to chemotherapeutic agents. Immunofluorescence staining revealed that the suppression of cell viability and induction of ER stress in ovarian cancer cells associated with an increase in the pro-apoptotic lipid ceramide. A specific inhibitor of ceramide de novo synthesis notably diminished endocannabinoid-induced ER stress. These data suggest that administration of endocannabinoids may be an effective way of treating ovarian tumors, with the underlying mechanism being the induction of the ceramide-dependent ER stress pathway.

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