Al-Bahlani Shadia, Al-Lawati Hanaa, Al-Adawi Moza, Al-Abri Nadia, Al-Dhahli Buthaina, Al-Adawi Kawther
Department of Allied Health Sciences, College of Medicine and Health Sciences, Sultan Qaboos University, P. O. Box 35, PC 123, Al Khoud, Oman.
Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, PC 123, Al Khoud, Oman.
Apoptosis. 2017 Jun;22(6):865-876. doi: 10.1007/s10495-017-1366-2.
Fatty acid synthase (FASN) is a key enzyme in fat biosynthesis that is over-expressed in advanced breast cancer stages. Cisplatin (CDDP) is a platinum-based drug used in the treatment of certain types of this disease. Although it was shown that FASN inhibition induced apoptosis by enhancing the cytotoxicity of certain drugs in breast cancer, its role in regulating the chemosensitivity of different types of breast cancer cells to CDDP-induced apoptosis is not established yet. Therefore, two different breast cancer cell lines; triple negative breast cancer (TNBC; MDA-MB-231) and triple positive breast cancer (TPBC; BT-474) cells were used to examine such role. We show that TNBC cells had naturally less fat content than TPBC cells. Subsequently, the fat content increased in both cells when treated with Palmitate rather than Oleate, whereas both fatty acids produced apoptotic ultra-structural effects and attenuated FASN expression. However, Oleate increased FASN expression in TPBC cells. CDDP decreased FASN expression and increased apoptosis in TNBC cells. These effects were further enhanced by combining CDDP with fatty acids. We also illustrate that the inhibition of FASN by either siRNA or exogenous inhibitor decreased CDDP-induced apoptosis in TPBC cells suggesting its role as an apoptotic factor, while an opposite finding was observed in TNBC cells when siRNA and fatty acids were used, suggesting its role as a survival factor. To our knowledge, we are the first to demonstrate a dual role of FASN in CDDP-induced apoptosis in breast cancer cells and how it can modulate their chemosensitivity.
脂肪酸合酶（FASN）是脂肪生物合成中的关键酶，在晚期乳腺癌阶段过度表达。顺铂（CDDP）是一种用于治疗某些类型该疾病的铂类药物。尽管研究表明FASN抑制通过增强某些药物在乳腺癌中的细胞毒性来诱导细胞凋亡，但其在调节不同类型乳腺癌细胞对CDDP诱导凋亡的化疗敏感性方面的作用尚未明确。因此，使用了两种不同的乳腺癌细胞系；三阴性乳腺癌（TNBC；MDA-MB-231）和三阳性乳腺癌（TPBC；BT-474）细胞来研究这种作用。我们发现TNBC细胞的天然脂肪含量低于TPBC细胞。随后，用棕榈酸而非油酸处理时，两种细胞的脂肪含量均增加，而两种脂肪酸均产生凋亡超微结构效应并减弱FASN表达。然而，油酸增加了TPBC细胞中FASN的表达。CDDP降低了TNBC细胞中FASN的表达并增加了细胞凋亡。将CDDP与脂肪酸联合使用可进一步增强这些效应。我们还表明，通过siRNA或外源性抑制剂抑制FASN可降低TPBC细胞中CDDP诱导的凋亡，表明其作为凋亡因子的作用，而当使用siRNA和脂肪酸时，在TNBC细胞中观察到相反的结果，表明其作为存活因子的作用。据我们所知，我们是第一个证明FASN在乳腺癌细胞中CDDP诱导的凋亡中的双重作用以及它如何调节其化疗敏感性的。
