F-circEA1 regulates cell proliferation and apoptosis through ALK downstream signaling pathway in non-small cell lung cancer

Studies have confirmed that circular RNA (circRNA) has a stable closed
structure, which plays an important role in the progression of tumors.
Cancers with positive fusion genes can produce associated fusion circRNA
(F-cirRNA). However, there are no reports concerning a role for
F-circRNA of the echinoderm microtubule associated-protein like
4-anaplastic lymphoma kinase variant 1 (EML4-ALK1) in non-small cell
lung cancer (NSCLC). Our study confirmed the existence of fusion circEA1
(F-circEA1) in NCI-H3122 cells (carrying the EML4-ALK1 gene), F-circEA1
was expressed both in the cytoplasm and nucleus as determined by
fluorescence in situ hybridization (FISH) and Sanger sequencing. CCK8
and transwell assays showed that F-circEA1 was beneficial to cell
proliferation, metastasis, and invasion. Overexpression of F-circEA1 can
also promote cell proliferation, migration and invasion in A549 and
SPCA1 cells (non-small cell lung cancer cell line not carrying the
EML4-ALK1 gene). Int..... READ ARTICLE

Human Cell DOI:10.1007/s13577-021-00628-7

Authors: Yinping Huo, Tangfeng Lv, Mingxiang Ye, Suhua Zhu, Jiaxin Liu, Hongbing Liu & Yong Song

Pre-Clinical, group2Kirk SmithOctober 11, 2021F-circEA1, EML4-ALK, NSCLC, Apoptosis

ZX-29, a novel ALK inhibitor, induces apoptosis via ER stress in ALK rearrangement NSCLC cells and overcomes cell resistance caused by an ALK mutation

Although anaplastic lymphoma kinase (ALK) inhibitors have good clinical efficacy, the inevitable development of drug resistance is the most common obstacle to their clinical application. There is an urgent need to develop more effective and selective ALK inhibitors to overcome the problem of drug resistance. Here, we screened a series of ALK inhibitors and found that ZX-29 displayed potent cytotoxic activity against ALK rearrangement non-small cell lung cancer (NSCLC) NCI-H2228 cells. Then, we investigated the antitumor effects of ZX-29. We demonstrated that ZX-29 time- and dose-dependently inhibited the viability of NCI-H2228 cells, induced cell cycle arrest in the G1 phase, and then they subsequently progressed into cell death. The type of cell death induced by ZX-29 was apoptosis through endoplasmic reticulum (ER) stress. Interestingly, ZX-29 induced protective autophagy, and inhibiting autophagy could enhance the antitumor effect of ZX-29. Furthermore, ZX-29 suppressed tumor growth..... READ ARTICLE

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research DOI:10.1016/j.bbamcr.2020.118712

Authors: Wenfeng Gou, Zengqiang Li, Xiaobo Xu, Jiwei Shen, Ming Guo, Xuejiao Zhou, Xiaoning Zhang, Yingliang Wu, Xin Zhai, Daiying Zuo

Pre-ClinicalKirk SmithJuly 1, 2020ALK, NSCLC, ER stress, Apoptosis, Drug resistance

Keratinocytes apoptosis contributes to crizotinib induced-erythroderma

Crizotinib is a multi-target receptor tyrosine kinase inhibitor which is of great importance for the management of ALK-rearranged non-small cell lung cancer (NSCLC) patients. Serious erythroderma and toxic epidermal necrolysis have been reported associated with crizotinib treatment. The underlying mechanisms have not been examined. In this study, we tested the toxicity of crizotinib on immortal human keratinocytes (HaCaT) and human primary keratinocytes. We found that crizotinib directly cause cytotoxic on these two cells, which could be the explanation of the clinical characteristic of pathology. Apoptosis was observed and Z-VAD-FMK, a pan-caspase inhibitor can almost totally reverse the apoptosis induction effect of crizotinib. However, mitochondrial dysfunction and DNA damage were not involved in crizotinib-induced apoptosis, indicating the intrinsic apoptosis pathway have no connection with this cutaneous toxicity. Further studies showed that crizotinib significantly increased clea..... READ ARTICLE

Toxicology Letters DOI:10.1016/j.toxlet.2019.11.007

Authors: Yuhuai Hu, Xiaochen Zhang, Ziying Zhao, Xueqin Chen, Ziye Zhou, Xiaochun Yang, Bo Yang, Qiaojun He, Peihua Luo

Review PaperKirk SmithFebruary 1, 2020Crizotinib, Cutaneous, toxicity, Erythroderma, Apoptosis, Cleaved-caspase-8

ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway

Crizotinib is an oral small-molecule tyrosine kinase inhibitor targeting anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) and MET proto-oncogene, receptor tyrosine kinase (MET). Unfortunately, hepatotoxicity is a serious limitation in its clinical application, and the reason remains largely unknown. In this study, we tested the effect of crizotinib in human hepatocyte cell line HL-7702 and human primary hepatocytes, and the results showed that crizotinib treatment caused hepatocyte damage, suggesting that crizotinib induced liver injury by causing hepatocyte death, consistent with the clinical cases. Mechanistically, crizotinib induced hepatocyte death via the apoptotic pathway, and cleaved PARP (c-PARP) was observed as a signaling protein. Moreover, mitochondrial membrane potential (MMP) decrease contributed to crizotinib-induced hepatocyte apoptosis accompanied by hepatocyte DNA damage and reactive oxygen species (ROS) generation. Importantly, crizotinib induced hepatocyte apoptosis independent of its targets, ALK, ROS1 and MET. In conclusion, our data showed that crizotinib induced liver injury through hepatocyte death via the apoptotic pathway which was independent of ALK, ROS1 and MET. And we also found that MMP decrease, DNA damage and ROS generation were involved in the process. READ ARTICLE

Toxicology and Applied Pharmacology DOI: 10.1016/j.taap.2019.114768

AUTHORS: Hao Yan, Jiangxia Du, Xueqin Chen, Bo Yang, Qiaojun He, Xiaochun Yang, Peihua Luo