RAC2-P38 MAPK-dependent NADPH oxidase activity is associated with the resistance of quiescent cells to ionizing radiation

Pei, Hailong; Zhang, Jian; Nie, Jing; Ding, Nan; Hu, Wentao; Hua, Junrui; Hirayama, Ryoichi; Furusawa, Yoshiya; Liu, Cuihua; Li, Bingyan; Hei, Tom K.; Zhou, Guangming

doi:10.1080/15384101.2016.1259039

Cited by 26 publications

(22 citation statements)

References 30 publications

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“…Increasing evidence supports that mitogen-activated protein kinases (MAPKs) mediate apoptosis and autophagy in response to chemotherapy. 19 , 20 MAPKs are key players in the regulation of cell proliferation and cancer development. Activation of p38 MAPK could augment the processes of apoptosis and autophagy.…”

mentioning

confidence: 99%

Escin induces caspase-dependent apoptosis and autophagy through the ROS/p38 MAPK signalling pathway in human osteosarcoma cells in vitro and in vivo

Zhu

Liu

et al. 2017

Cell Death Dis

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Osteosarcoma is one of the most malignant neoplasms in adolescents, and it generally develops multidrug resistance. Escin, a natural mixture of triterpene saponins isolated from Aesculus hippocastanum (horse chestnut), has demonstrated potent anti-tumour potential in vitro and in vivo. In the present study, we found that escin inhibited osteosarcoma proliferation in a dose- and time-dependent manner. Additionally, escin-induced apoptosis was evidenced by the increased expression of caspase-related proteins and the formation of apoptotic bodies. Escin also induced autophagy, with elevated LC3, ATG5, ATG12 and Beclin expression as well as autophagosome formation. Inhibition of escin-induced autophagy promoted apoptosis. Moreover, p38 mitogen-activated protein kinases (MAPKs) and reactive oxygen species (ROS) were activated by escin. A p38 MAPK inhibitor partially attenuated the autophagy and apoptosis triggered by escin, but a ROS scavenger showed a greater inhibitory effect. Finally, the therapeutic efficacy of escin against osteosarcoma was demonstrated in an orthotopic model. Overall, escin counteracted osteosarcoma by inducing autophagy and apoptosis via the activation of the ROS/p38 MAPK signalling pathway; these findings provide evidence for escin as a novel and potent therapeutic for the treatment of osteosarcoma.

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mentioning

confidence: 99%

Escin induces caspase-dependent apoptosis and autophagy through the ROS/p38 MAPK signalling pathway in human osteosarcoma cells in vitro and in vivo

Zhu

Liu

et al. 2017

Cell Death Dis

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“…A study showed that baseline MAPK signaling activity conferred intrinsic radioresistance to KRAS-mutant colorectal carcinoma cells by rapid up-regulation of hnRNP K ( Eder et al, 2017 ). Moreover, quiescent G0 cells were found to be more resistant to ionizing radiation than G1 cells because P38 MAPK , phosphorylated P38 MAPK , and RAC2 were regulated in mutual feedback and negative feedback regulatory pathways, leading to the radioresistance of G0 cells ( Pei et al, 2017 ). Interestingly, RPS6KA5 , RPS6KA6 , CRKL , RAP1A , FASLG , and MAPK8 were found in both MAPK and neurotrophin signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive circular RNA expression profile in radiation-treated HeLa cells and analysis of radioresistance-related circRNAs

Ming

et al. 2018

PeerJ

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BackgroundCervical cancer is one of the most common cancers in women worldwide. Malignant tumors develop resistance mechanisms and are less sensitive to or do not respond to irradiation. With the development of high-throughput sequencing technologies, circular RNA (circRNA) has been identified in an increasing number of diseases, especially cancers. It has been reported that circRNA can compete with microRNAs (miRNAs) to change the stability or translation of target RNAs, thus regulating gene expression at the transcriptional level. However, the role of circRNAs in cervical cancer and the radioresistance mechanisms of HeLa cells are unknown. The objective of this study is to investigate the role of circRNAs in radioresistance in HeLa cells.MethodsHigh-throughput sequencing and bioinformatics analysis of irradiated and sham-irradiated HeLa cells. The reliability of high-throughput RNA sequencing was validated using quantitative real-time polymerase chain reaction. The most significant circRNA functions and pathways were selected by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A circRNA–miRNA–target gene interaction network was used to find circRNAs associated with radioresistance. Moreover, a protein–protein interaction network was constructed to identify radioresistance-related hub proteins.ResultsHigh-throughput sequencing allowed the identification of 16,893 circRNAs involved in the response of HeLa cells to radiation. Compared with the control group, there were 153 differentially expressed circRNAs, of which 76 were up-regulated and 77 were down-regulated. GO covered three domains: biological process (BP), cellular component (CC) and molecular function (MF). The terms assigned to the BP domain were peptidyl-tyrosine dephosphorylation and regulation of cell migration. The identified CC terms were cell–cell adherens junction, nucleoplasm and cytosol, and the identified MF terms were protein binding and protein tyrosine phosphatase activity. The top five KEGG pathways were MAPK signaling pathway, endocytosis, axon guidance, neurotrophin signaling pathway, and SNARE interactions in vesicular transport. The protein–protein interaction analysis indicated that 19 proteins might be hub proteins.ConclusionsCircRNAs may play a major role in the response to radiation. These findings may improve our understanding of the role of circRNAs in radioresistance in HeLa cells and allow the development of novel therapeutic approaches.

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“…Phosphorylation of P38 MAPK enhanced cellular radioresistance. However, excessive ROS production led to P38 MAPK dephosphorylation, suggesting that the ROS/RAC2/P38 MAPK feedback loop generates quiescent cells more resistant to ionizing radiation (IR) [13]. These findings reveal a new paradigm for understanding radioresistance of G0 cells and support the potential application of RAC2 inhibitors as radiation protectants.…”

Section: Strategies To Improve Radioresistance Of Quiescent Tumor Cellsmentioning

confidence: 91%

“…Although the protected state is favorable for long-term maintenance of the quiescent state, activation of these pathways in tumor cells may play a crucial role in higher resistance to conventional cancer therapies that largely target proliferating cells [3,5,11,12]. Quiescent tumor cells are considered significantly less radio/ chemosensitive with a greater repair capacity than cycling cells [11,13,14]. Resistance of G0 cells from breast, pancreatic, ovarian tumors and squamous cell carcinomas to traditional therapeutic patterns has been reported [3,15].…”

Section: Quiescent Tumor Cells Represent a Clinical Problemmentioning

confidence: 99%

“…RAC2 induces aberrant proliferation of quiescent non-small cell lung cancer cells (NSCLC) via promoting JUNB expression through the MAL-SRF pathway [89]. Moreover, earlier studies have reported that low expression of RAC2 in G0 cells accounts for cellular radioresistance through suppression of NAPDH oxidase activity, which results in low yields of ROS and high antioxidant activity [13]. P38 MAPK interactions with RAC2 induced a decrease in functional RAC2.…”

Section: Strategies To Improve Radioresistance Of Quiescent Tumor Cellsmentioning

confidence: 99%

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Research progress on therapeutic targeting of quiescent cancer cells

Zhang

Gan

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Cellular quiescence (G0) is a sleep-like cellular state that allows cells to maintain the ability to re-enter and exit the proliferative cycle. Quiescent cancer cells are considered a therapeutic challenge since they are often resistant to conventional chemoradiotherapy resulting in disease progression and relapse. To date, the majority of published studies have focused on identifying molecules that target proliferating tumor cells while limited information is available on methods to target quiescent cancer cells. This review provides a summary of the relevant molecular mechanisms underlying quiescence maintenance and pharmacological interventions aimed at either eliminating this cancer cell subpopulation or indefinitely maintaining the quiescence state. Furthermore, the irradiation responses of quiescent cancer cells, in particular, the influence of manipulating intratumor hypoxia and radiation properties on radiosensitivity, are discussed. The main aim of this article is to provide a theoretical basis for the effective targeted killing of dormant tumor cells. ARTICLE HISTORY

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RAC2-P38 MAPK-dependent NADPH oxidase activity is associated with the resistance of quiescent cells to ionizing radiation

Cited by 26 publications

References 30 publications

Escin induces caspase-dependent apoptosis and autophagy through the ROS/p38 MAPK signalling pathway in human osteosarcoma cells in vitro and in vivo

Escin induces caspase-dependent apoptosis and autophagy through the ROS/p38 MAPK signalling pathway in human osteosarcoma cells in vitro and in vivo

Comprehensive circular RNA expression profile in radiation-treated HeLa cells and analysis of radioresistance-related circRNAs

Research progress on therapeutic targeting of quiescent cancer cells

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