Rath Suvasmita, Das Lopamudra, Kokate Shrikant Babanrao, Ghosh Nilabh, Dixit Pragyesh, Rout Niranjan, Singh Shivaram P, Chattopadhyay Subhasis, Ashktorab Hassan, Smoot Duane T, Swamy Mahadeva M, Kundu Tapas K, Crowe Sheila E, Bhattacharyya Asima
School of Biological Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, HBNI, P.O. Bhimpur-Padanpur, Via Jatni, Dist. Khurda, 752050, Odisha, India.
Oncopathology, Acharya Harihar Regional Cancer Centre, Cuttack, 753007, Odisha, India.
Int J Biochem Cell Biol. 2017 Jan;82:28-40. doi: 10.1016/j.biocel.2016.11.014. Epub 2016 Nov 23.
Hypoxia enhances immortality and metastatic properties of solid tumors. Deregulation of histone acetylation has been associated with several metastatic cancers but its effect on hypoxic responses of cancer cells is not known. This study aimed at understanding the effectiveness of the hydrazinocurcumin, CTK7A, an inhibitor of p300 lysine/histone acetyltransferase (KAT/HAT) activity, in inducing apoptosis of gastric cancer cells (GCCs) exposed to cobalt chloride (CoCl), a hypoxia-mimetic chemical, or 1% O. Here, we show that CTK7A-induced hydrogen peroxide (HO) generation in CoCl-exposed and invasive gastric cancer cells (GCCs) leads to p38 MAPK-mediated Noxa expression and thereafter, mitochondrial apoptotic events. Noxa induction in normal immortalized gastric epithelial cells after CTK7A and hypoxia-exposure is remarkably less in comparison to similarly-treated GCCs. Moreover, hypoxia-exposed GCCs, which have acquired invasive properties, become apoptotic after CTK7A treatment to a significantly higher extent than normoxic cells. Thus, we show the potential of CTK7A in sensitizing hypoxic and metastatic GCCs to apoptosis induction.
缺氧增强实体瘤的永生性和转移特性。组蛋白乙酰化失调与多种转移性癌症相关，但其对癌细胞缺氧反应的影响尚不清楚。本研究旨在了解肼基姜黄素CTK7A（一种p300赖氨酸/组蛋白乙酰转移酶（KAT/HAT）活性抑制剂）对暴露于氯化钴（CoCl，一种缺氧模拟化学物质）或1%氧气的胃癌细胞（GCCs）诱导凋亡的有效性。在此，我们表明CTK7A在暴露于CoCl的侵袭性胃癌细胞（GCCs）中诱导过氧化氢（HO）生成，导致p38丝裂原活化蛋白激酶（MAPK）介导的Noxa表达，进而引发线粒体凋亡事件。与同样处理的GCCs相比，CTK7A和缺氧暴露后正常永生化胃上皮细胞中的Noxa诱导明显较少。此外，具有侵袭特性的缺氧暴露GCCs在CTK7A处理后比常氧细胞更易发生凋亡，且程度显著更高。因此，我们展示了CTK7A在使缺氧和转移性GCCs对凋亡诱导敏感方面的潜力。
