Department of Surgery, Chungnam National University Hospital, Daejeon 301–721, Korea.
Biol Pharm Bull. 2012;35(1):105-10. doi: 10.1248/bpb.35.105.
AMP-activated protein kinase (AMPK) is a sensor of cellular energy status found in all eukaryotes. Recent studies indicate that AMPK activation strongly suppresses cell proliferation in tumor cells, which requires high rates of protein synthesis and de novo fatty acid synthesis for their rapid growth. Pomolic acid (PA) has been previously described as being active in inhibiting the growth of cancer cells. In this study, we investigated PA activated AMPK, and this activity was related to proliferation and apoptosis in MCF7 breast cancer cells. PA inhibited cell proliferation and induced sub-G(1) arrest, elevating the mRNA levels of the apoptotic genes p53 and p21. PA activated caspase-3, -9, and poly(ADP-ribose) polymerase, and this effect was inhibited by z-VAD-fmk. AMPK activation was increased by treating cells with PA, inactivated by treating cells with a compound C, and co-treatment consisting of PA and aminoimidazole carboxamide ribonucleotide (AICAR) synergistically activated AMPK. These anti-cancer potentials of PA were accompanied by effects on de novo fatty acid synthesis as shown by the decreased expression of fatty acid synthase, and decreased acetyl-CoA carboxylase activation and incorporation of [(3)H]acetyl-CoA into fatty acids. In addition, PA inhibited key enzymes involved in protein synthesis such as mammalian target of rapamycin (mTOR), 70 kDa ribosomal protein S6 kinase (p70S6K), and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). These results suggest that PA exerts anti-cancer properties through the modulation of AMPK pathways and its value as an anti-cancer agent in breast cancer therapy.
腺苷酸活化蛋白激酶（AMPK）是一种存在于所有真核生物中的细胞能量状态传感器。最近的研究表明，AMPK 的激活强烈抑制肿瘤细胞的增殖，这需要高蛋白质合成率和从头脂肪酸合成率来支持其快速生长。熊果酸（PA）先前被描述为能有效抑制癌细胞生长。在这项研究中，我们研究了 PA 激活的 AMPK，这种活性与 MCF7 乳腺癌细胞的增殖和凋亡有关。PA 抑制细胞增殖并诱导 sub-G1 期阻滞，提高凋亡基因 p53 和 p21 的 mRNA 水平。PA 激活半胱天冬酶-3、-9 和聚（ADP-核糖）聚合酶，该作用被 z-VAD-fmk 抑制。用 PA 处理细胞可增加 AMPK 的激活，用化合物 C 处理细胞可使其失活，并用 PA 和氨基咪唑羧酰胺核苷酸（AICAR）共同处理可协同激活 AMPK。PA 的这些抗癌潜力伴随着从头脂肪酸合成的影响，如脂肪酸合酶表达降低、乙酰辅酶 A 羧化酶激活降低和 [(3)H]乙酰辅酶 A 掺入脂肪酸。此外，PA 抑制了参与蛋白质合成的关键酶，如哺乳动物雷帕霉素靶蛋白（mTOR）、70 kDa 核糖体蛋白 S6 激酶（p70S6K）和真核翻译起始因子 4E 结合蛋白 1（4EBP1）。这些结果表明，PA 通过调节 AMPK 通路发挥抗癌特性，并且在乳腺癌治疗中具有作为抗癌剂的价值。
