Kim Wootae, Jeong Joo-Won, Kim Ja-Eun
Department of Pharmacology, School of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea.
Tumour Biol. 2014 Nov;35(11):10919-29. doi: 10.1007/s13277-014-2370-6. Epub 2014 Aug 2.
Melatonin exhibits oncostatic activity in several cancers but does not lead to cytotoxicity in estrogen receptor (ER)-negative non-small cell lung cancers (NSCLCs). In an effort to overcome the melatonin resistance of these cancers, we investigated whether cell cycle and apoptosis regulator 2 (CCAR2) depletion would promote apoptosis following genotoxic stress in melatonin-resistant cancer cells. Ordinarily, the NSCLC cell lines A549 and A427 did not undergo cell death following melatonin treatment for short period. These cell lines were irradiated with UV, a source of genotoxic damage, to trigger apoptotic signaling. Treatment with melatonin prior to irradiation did not produce any significant change in apoptosis. By contrast, in CCAR2-deficient cells, melatonin treatment increased apoptosis induced by genotoxic stress; this effect was dependent on the dose of melatonin. The increase in apoptosis in CCAR2-deficient cells was not dependent on SIRT1. The results indicate that CCAR2 is critical for maintaining cell survival in the presence of melatonin under genotoxic stress. Furthermore, CCAR2 is overexpressed in NSCLC; therefore, melatonin could be used as a potential supplement to classical anticancer drugs in therapies against CCAR2-deficient cancers.
褪黑素在多种癌症中表现出抑癌活性，但对雌激素受体（ER）阴性的非小细胞肺癌（NSCLC）不会产生细胞毒性。为了克服这些癌症的褪黑素耐药性，我们研究了在耐褪黑素的癌细胞中，敲低细胞周期和凋亡调节因子2（CCAR2）是否会在基因毒性应激后促进细胞凋亡。通常情况下，NSCLC细胞系A549和A427在短期褪黑素处理后不会发生细胞死亡。用紫外线（一种基因毒性损伤源）照射这些细胞系，以触发凋亡信号。照射前用褪黑素处理对细胞凋亡没有产生任何显著变化。相比之下，在CCAR2缺陷细胞中，褪黑素处理增加了基因毒性应激诱导的细胞凋亡；这种效应取决于褪黑素的剂量。CCAR2缺陷细胞中细胞凋亡的增加不依赖于沉默调节蛋白1（SIRT1）。结果表明，在基因毒性应激下，CCAR2对于在褪黑素存在的情况下维持细胞存活至关重要。此外，CCAR2在NSCLC中过表达；因此，褪黑素可作为一种潜在的补充药物，与传统抗癌药物联合用于治疗CCAR2缺陷型癌症。
