Leipert Jenny, Kässner Franziska, Schuster Susanne, Händel Norman, Körner Antje, Kiess Wieland, Garten Antje
a Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig , Leipzig , Germany.
b Leipzig University Medical Center, IFB Adiposity Diseases Leipzig , Leipzig , Germany.
Nutr Cancer. 2016;68(2):342-9. doi: 10.1080/01635581.2016.1145244. Epub 2016 Mar 4.
Patients with phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome and germline mutations in PTEN frequently develop lipomatosis, for which there is no standard treatment. Rapamycin was shown to reduce the growth of lipoma cells with heterozygous PTEN deficiency in vitro, but concomitantly induced an upregulation of AKT phosphorylation. Since it was shown that resveratrol stabilizes PTEN, we asked whether co-incubation with resveratrol could suppress the rapamycin-induced AKT phosphorylation in PTEN-deficient lipoma cells. Resveratrol incubation resulted in decreased lipoma cell viability by inducing G1-phase cell cycle arrest and apoptosis. PTEN expression and AKT phosphorylation were not significantly changed, whereas p70S6 kinase (p70S6K) phosphorylation was reduced in PTEN-deficient lipoma cells after resveratrol incubation. Rapamycin/resveratrol co-incubation significantly decreased viability further at lower doses of resveratrol and resulted in decreased p70S6K phosphorylation compared to rapamycin incubation alone, suggesting that resveratrol potentiated the growth inhibitory effects of rapamycin by reducing p70S6K activation. Both viability and p70S6K phosphorylation of primary PTEN wild-type preadipocytes were less affected compared to PTEN-deficient lipoma cells by equimolar concentrations of resveratrol. These results support the concept of combining chemopreventive natural compounds with mammalian target of rapamycin (mTOR) inhibitors to increase the efficacy of chemotherapeutic drugs for patients suffering from overgrowth syndromes.
患有磷酸酶和张力蛋白同源物（PTEN）错构瘤肿瘤综合征且PTEN存在种系突变的患者经常会发生脂肪瘤病，对此尚无标准治疗方法。雷帕霉素在体外可减少杂合型PTEN缺陷的脂肪瘤细胞的生长，但同时会诱导AKT磷酸化上调。由于已表明白藜芦醇可稳定PTEN，我们探究了与白藜芦醇共同孵育是否能抑制雷帕霉素诱导的PTEN缺陷型脂肪瘤细胞中的AKT磷酸化。白藜芦醇孵育通过诱导G1期细胞周期停滞和凋亡导致脂肪瘤细胞活力下降。PTEN表达和AKT磷酸化无显著变化，而白藜芦醇孵育后PTEN缺陷型脂肪瘤细胞中的p70S6激酶（p70S6K）磷酸化降低。雷帕霉素/白藜芦醇共同孵育在较低剂量白藜芦醇时能进一步显著降低细胞活力，且与单独使用雷帕霉素孵育相比导致p70S6K磷酸化降低，这表明白藜芦醇通过降低p70S6K激活增强了雷帕霉素的生长抑制作用。与PTEN缺陷型脂肪瘤细胞相比，等摩尔浓度的白藜芦醇对原代PTEN野生型前脂肪细胞的活力和p70S6K磷酸化影响较小。这些结果支持将化学预防天然化合物与雷帕霉素哺乳动物靶点（mTOR）抑制剂联合使用以提高化疗药物对患有过度生长综合征患者疗效的概念。
