探討不飽和脂肪酸對於人類乳癌細胞脂肪酸合成酶之可能調控路徑

Abstract

乳癌細胞常伴隨著脂肪酸合成酶的過度表現以提升細胞內脂肪酸合成，並形成細胞增生時所需的磷脂質來源。二十二碳六烯酸（DHA）以及二十碳四烯酸（AA）對於腫瘤行常常扮演相反角色，如在生長方面DHA 可抑制細胞生長，而AA 則具有促進效果，但目前詳細機制不明。本實驗中假設造成此相反現象可能是經由透過調控脂肪酸合成酶所導致，因此將MCF-7 細胞培養在含0、10、60μM AA、OA 以及DHA 48 小時後，再利用胰島素刺激一小時，結果可得處理60μM DHA 可使脂肪酸合成酶表現量下降，並使細胞內Akt 磷酸化現象下降；且在IC50 測試中，60μM DHA 處理之下可以降低脂肪酸合成酶抑制劑Cerulenin 的使用量，並且可加強抑制細胞存活率的效果。但在10μM DHA 或10、60μM AA 以及OA 沒有此效果。綜合以上結果可得，DHA 可能透過調控脂肪酸合成酶表現降低乳癌細胞存活率，並且與Cerulenin 對於抑制細胞存活率具有協同效應。

Fatty acid synthase (FAS) is up regulated in breast cancer for the de novo biosynthesis of fatty acids mainly to be incorporated into phospholipids for the cell proliferation. Docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) have opposites on carcinogenesis, with DHA suppressing and AA promoting breast cancer growth. However, the mechanism is not clear. We examined whether the effect is mediated through changes FAS expression. MCF-7 cells were cultured in normal medium containing 0, 10 or 60 mM DHA, AA or oleic acid (OA, 18:1n-9) for 48 hrs, then were stimulated with 1 mg/ml insulin. 60 mM DHA supplementation resulted in down regulation of FAS expression, a reduction on phosphorylated Akt, a decrease in the IC50 of FAS inhibitor cerulenin and enhancing cerulenin-induced viability inhibition in MCF-7. In contrast, 10 mM DHA, 10 or 60mM AA and OA had no such effects. We propose that breast cancer cell viability is inhibited by DHA through down regulation of FAS expression and DHA has a synergistic effect on FAS inhibitor for the breast cancer therapy.