Jeon Min Ji, Kim Won Gu, Lim Seonhee, Choi Hyun-Jeung, Sim Soyoung, Kim Tae Yong, Shong Young Kee, Kim Won Bae
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Asan Institute of Life Sciences, Seoul, South Korea.
Mol Cell Endocrinol. 2016 Jan 5;419:113-23. doi: 10.1016/j.mce.2015.10.005. Epub 2015 Oct 14.
The naturally occurring short-chain fatty acid, α-lipoic acid (ALA) is a powerful antioxidant which is clinically used for treatment of diabetic neuropathy. Recent studies suggested the possibility of ALA as a potential anti-cancer agent, because it could activate adenosine monophosphate activated protein kinase (AMPK) and inhibit transforming growth factor-β (TGFβ) pathway. In this study, we evaluate the effects of ALA on thyroid cancer cell proliferation, migration and invasion. We performed in vitro cell proliferation analysis using BCPAP, HTH-83, CAL-62 and FTC-133 cells. ALA suppressed thyroid cancer cell proliferation through activation of AMPK and subsequent down-regulation of mammalian target of rapamycin (mTOR)-S6 signaling pathway. Low-dose ALA, which had minimal effects on cell proliferation, also decreased cell migration and invasion of BCPAP, CAL-62 and HTH-83 cells. ALA inhibited epithelial mesenchymal transition (EMT) evidently by increase of E-cadherin and decreases of activated β-catenin, vimentin, snail, and twist in these cells. ALA suppressed TGFβ production and inhibited induction of p-Smad2 and twist by TGFβ1 or TGFβ2. These findings indicate that ALA reduces cancer cell migration and invasion through suppression of TGFβ production and inhibition of TGFβ signaling pathways in thyroid cancer cells. ALA also significantly suppressed tumor growth in mouse xenograft model using BCPAP and FTC-133 cells. This is the first study to show anti-cancer effect of ALA on thyroid cancer cells. ALA could be a potential therapeutic agent for treatment of advanced thyroid cancer, possibly as an adjuvant therapy with other systemic therapeutic agents.
天然存在的短链脂肪酸α-硫辛酸（ALA）是一种强大的抗氧化剂，临床上用于治疗糖尿病性神经病变。最近的研究表明，ALA有可能成为一种潜在的抗癌药物，因为它可以激活单磷酸腺苷激活蛋白激酶（AMPK）并抑制转化生长因子-β（TGFβ）信号通路。在本研究中，我们评估了ALA对甲状腺癌细胞增殖、迁移和侵袭的影响。我们使用BCPAP、HTH-83、CAL-62和FTC-133细胞进行了体外细胞增殖分析。ALA通过激活AMPK并随后下调雷帕霉素哺乳动物靶蛋白（mTOR）-S6信号通路来抑制甲状腺癌细胞增殖。低剂量的ALA对细胞增殖影响极小，但也减少了BCPAP、CAL-62和HTH-83细胞的迁移和侵袭。ALA通过增加E-钙黏蛋白并降低这些细胞中活化的β-连环蛋白、波形蛋白、蜗牛蛋白和Twist蛋白的表达，明显抑制上皮-间质转化（EMT）。ALA抑制TGFβ的产生，并抑制TGFβ1或TGFβ2诱导的p-Smad2和Twist蛋白的表达。这些发现表明，ALA通过抑制甲状腺癌细胞中TGFβ的产生和TGFβ信号通路来减少癌细胞的迁移和侵袭。ALA在使用BCPAP和FTC-133细胞的小鼠异种移植模型中也显著抑制了肿瘤生长。这是第一项显示ALA对甲状腺癌细胞具有抗癌作用的研究。ALA可能作为一种与其他全身治疗药物联合使用的辅助治疗方法，成为晚期甲状腺癌治疗的潜在治疗药物。
