Rho Seung Bae, Byun Hyun Jung, Kim Boh-Ram, Lee Chang Hoon
Division of Translational Science, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea.
BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 10326, Republic of Korea.
Biomol Ther (Seoul). 2021 Nov 1;29(6):650-657. doi: 10.4062/biomolther.2021.131.
Metformin is an anti-diabetic drug and has anticancer effects on various cancers. Several studies have suggested that metformin reduces cell proliferation and stimulates cell-cycle arrest and apoptosis. However, the definitive molecular mechanism of metformin in the pathophysiological signaling in endometrial tumorigenesis and metastasis is not clearly understood. In this study, we examined the effects of metformin on the cell viability and apoptosis of human cervical HeLa and endometrial HEC-1-A and KLE cancer cells. Metformin suppressed cell growth in a dose-dependent manner and dramatically evoked apoptosis in HeLa cervical cancer cells, while apoptotic cell death and growth inhibition were not observed in endometrial (HEC-1-A, KLE) cell lines. Accordingly, the p27 and p21 promoter activities were enhanced while Bcl-2 and IL-6 activities were significantly reduced by metformin treatment. Metformin diminished the phosphorylation of mTOR, p70S6K and 4E-BP1 by accelerating adenosine monophosphateactivated kinase (AMPK) in HeLa cancer cells, but it did not affect other cell lines. To determine why the anti-proliferative effects are observed only in HeLa cells, we examined the expression level of liver kinase B1 (LKB1) since metformin and LKB1 share the same signalling system, and we found that the gene is not expressed only in HeLa cancer cells. Consistently, the overexpression of LKB1 in HeLa cancer cells prevented metformin-triggered apoptosis while knockdown significantly increased apoptosis in HEC-1-A and KLE cancer cells. Taken together, these findings indicate an underlying biological/physiological molecular function specifically for metformin-triggered apoptosis dependent on the presence of the gene in tumorigenesis.
二甲双胍是一种抗糖尿病药物，对多种癌症具有抗癌作用。多项研究表明，二甲双胍可减少细胞增殖，刺激细胞周期停滞和凋亡。然而，二甲双胍在子宫内膜肿瘤发生和转移的病理生理信号传导中的明确分子机制尚不清楚。在本研究中，我们检测了二甲双胍对人宫颈HeLa细胞以及子宫内膜HEC-1-A和KLE癌细胞的细胞活力和凋亡的影响。二甲双胍以剂量依赖性方式抑制细胞生长，并显著诱导HeLa宫颈癌细胞凋亡，而在子宫内膜（HEC-1-A、KLE）细胞系中未观察到凋亡细胞死亡和生长抑制。因此，二甲双胍处理可增强p27和p21启动子活性，同时显著降低Bcl-2和IL-6活性。二甲双胍通过加速HeLa癌细胞中的腺苷单磷酸激活激酶（AMPK）来减少mTOR、p70S6K和4E-BP1的磷酸化，但对其他细胞系没有影响。为了确定为何仅在HeLa细胞中观察到抗增殖作用，我们检测了肝脏激酶B1（LKB1）的表达水平，因为二甲双胍和LKB1共享相同的信号系统，并且我们发现该基因仅在HeLa癌细胞中不表达。一致地，HeLa癌细胞中LKB1的过表达可阻止二甲双胍触发的凋亡，而敲低则显著增加HEC-1-A和KLE癌细胞中的凋亡。综上所述，这些发现表明在肿瘤发生过程中，二甲双胍触发的凋亡存在一种特定的潜在生物学/生理分子功能，该功能依赖于该基因的存在。
