Kim Si Hyoung, Kang Jun Goo, Kim Chul Sik, Ihm Sung-Hee, Choi Moon Gi, Yoo Hyung Joon, Lee Seong Jin
Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
Tumour Biol. 2017 May;39(5):1010428317698369. doi: 10.1177/1010428317698369.
The influence of celastrol alone or in combination with paclitaxel on survival of anaplastic thyroid carcinoma cells was investigated. In 8505C and SW1736 cells, after treatment of celastrol, cell viability decreased, and cytotoxic activity increased. The protein levels of heat shock protein (hsp) 90, hsp70, Bax, death receptor 5, cleaved caspase-3, cleaved poly (ADP-ribose) polymerase, phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), and phospho-c-Jun N-terminal kinase (JNK) were elevated, and those of Bcl2, phospho-nuclear factor-kappaB (NF-κB), and total and phospho-Akt were reduced. The endoplasmic reticulum stress markers expression and reactive oxygen species production were enhanced. In celastrol-treated cells, N-acetylcysteine increased cell viability and phospho-NF-κB protein levels, and decreased reactive oxygen species production and cytotoxic activity. The protein levels of cyclooxygenase 2, phospho-ERK1/2, phospho-JNK and Bip were diminished. After treatment of both celastrol and paclitaxel, compared with paclitaxel alone, cell viability and the percentage of viable cells were reduced, and death rate and cytotoxic activity were elevated. The protein levels of phospho-ERK1/2, phospho-JNK, Bip, and cyclooxygenase 2, and reactive oxygen species production were enhanced. All of the Combination Index values calculated by Chou-Talalay equation were lower than 1.0, implying the synergism between celastrol and paclitaxel in induction of cell death. In conclusion, our results suggest that celastrol induces cytotoxicity through involvement of Bcl2 family proteins and death receptor, and modulation of phospho-NF-κB, Akt, and mitogen-activated protein kinase in association with endoplasmic reticulum stress and reactive oxygen species production in anaplastic thyroid carcinoma cells. Moreover, celastrol synergizes with paclitaxel in induction of cytotoxicity in anaplastic thyroid carcinoma cells.
研究了雷公藤红素单独或与紫杉醇联合使用对间变性甲状腺癌细胞存活的影响。在8505C和SW1736细胞中，雷公藤红素处理后，细胞活力降低，细胞毒性活性增加。热休克蛋白（hsp）90、hsp70、Bax、死亡受体5、裂解的半胱天冬酶-3、裂解的聚（ADP-核糖）聚合酶、磷酸化细胞外信号调节激酶1/2（ERK1/2）和磷酸化c-Jun氨基末端激酶（JNK）的蛋白水平升高，而Bcl2、磷酸化核因子-κB（NF-κB）以及总Akt和磷酸化Akt的蛋白水平降低。内质网应激标志物表达和活性氧生成增加。在雷公藤红素处理的细胞中，N-乙酰半胱氨酸增加了细胞活力和磷酸化NF-κB蛋白水平，并降低了活性氧生成和细胞毒性活性。环氧合酶2、磷酸化ERK1/2、磷酸化JNK和Bip的蛋白水平降低。在雷公藤红素和紫杉醇联合处理后，与单独使用紫杉醇相比，细胞活力和活细胞百分比降低，死亡率和细胞毒性活性升高。磷酸化ERK1/2、磷酸化JNK、Bip和环氧合酶2的蛋白水平以及活性氧生成增加。通过Chou-Talalay方程计算的所有联合指数值均低于1.0，这意味着雷公藤红素和紫杉醇在诱导细胞死亡方面具有协同作用。总之，我们的结果表明，雷公藤红素通过Bcl2家族蛋白和死亡受体的参与，以及与间变性甲状腺癌细胞内质网应激和活性氧生成相关的磷酸化NF-κB、Akt和丝裂原活化蛋白激酶的调节来诱导细胞毒性。此外，雷公藤红素与紫杉醇在诱导间变性甲状腺癌细胞毒性方面具有协同作用。
