Nuclear accumulation of KPNA2 impacts radioresistance through positive regulation of the PLSCR1‐STAT1 loop in lung adenocarcinoma

Liao, Wei; Lin, Tsung-Jen; Liu, Yu-Chin; Wei, Yu‐Shan; Chen, Guanying; Feng, Hsiang-Pu; Chang, Yi-Feng; Chang, Hsin-Tzu; Wang, Chih‐Liang; Chi, Hsinag-Cheng; Wang, Chun-I; Lin, Kwang‐Huei; Yang, Wei-Ting Ou; Yu, Chia‐Jung

doi:10.1111/cas.15197

Cited by 10 publications

(6 citation statements)

References 61 publications

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“…9,42 We reported that AKT1 knockdown attenuated the nuclear accumulation of KPNA2 in radioresistant lung cancer cells. 44 Our recent study found that acetylation of KPNA2 at lysine 22 and phosphorylation at serine 105 regulate the migration and nucleocytoplasmic distribution of KPNA2 in lung adenocarcinomas cells, 27 suggesting that post-translational modifications of KPNA2 are important in cancer biology. Based on mass spectrometry analyses, quantitative tissue phosphoproteome studies showed that KPNA2 phosphorylation at S62 was higher in breast cancer tissues 45,46 and colon cancer tissues 47 than in normal tissues.…”

Section: Discussionmentioning

confidence: 98%

Oxidative stress mediates nucleocytoplasmic shuttling of KPNA2 via AKT1‐CDK1 axis‐regulated S62 phosphorylation

Huang,

Wang,

Kuo

et al. 2024

FASEB BioAdvances

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Karyopherin α 2 (KPNA2, importin α1), a transport factor shuttling between the nuclear and cytoplasmic compartments, is involved in the nuclear import of proteins and participates in cellular processes such as cell cycle regulation, apoptosis, and transcriptional regulation. However, it is still unclear which signaling regulates the nucleocytoplasmic distribution of KPNA2 in response to cellular stress. In this study, we report that oxidative stress increases nuclear retention of KPNA2 through alpha serine/threonine‐protein kinase (AKT1)‐mediated reduction of serine 62 (S62) phosphorylation. We first found that AKT1 activation was required for H2O2‐induced nuclear accumulation of KPNA2. Immunoprecipitation and quantitative proteomic analysis revealed that the phosphorylation of KPNA2 at S62 was decreased under H2O2‐induced oxidative stress. We showed that cyclin‐dependent kinase 1 (CDK1), a kinase responsible for KPNA2 S62 phosphorylation, contributes to the localization of KPNA2 in the cytoplasm. AKT1 knockdown increased KPNA2 S62 phosphorylation and inhibited CDK1 activation. Furthermore, H2O2‐induced AKT1 activation promoted nuclear KPNA2 interaction with nucleophosmin 1 (NPM1), resulting in attenuation of NPM1‐mediated cyclin D1 gene transcription. Thus, we infer that the AKT1‐CDK1 axis regulates the nucleocytoplasmic shuttling and function of KPNA2 through spatiotemporal regulation of KPNA2 S62 phosphorylation under oxidative stress conditions.

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Section: Discussionmentioning

confidence: 98%

Oxidative stress mediates nucleocytoplasmic shuttling of KPNA2 via AKT1‐CDK1 axis‐regulated S62 phosphorylation

Huang,

Wang,

Kuo

et al. 2024

FASEB BioAdvances

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“…Based on current evidence, it is difficult to predict when PLSCR1 overexpression or inhibition would be beneficial in human disease since PLSCR1 function may vary according to cell types and disease processes. Nevertheless, a number of reports have highlighted the possible beneficial effects of PLSCR1 targeting in colorectal cancers, hepatic cancers, and lung adenocarcinoma, where blockade or silencing of this protein resulted in the inhibition of tumor growth and metastasis [ 19 , 79 , 80 , 91 ].…”

Section: Discussionmentioning

confidence: 99%

“…This PLSCR1-STAT3 axis was confirmed by Liao et al . , who demonstrated that karyopherin-α2 promoted radioresistance in lung adenocarcinoma by boosting PLSCR1-STAT3-mediated induction of STAT1-dependent signaling [ 79 ]. In a pilot study by Huang et al .…”

Section: Plscr1 Interactions With Endogenous Proteinsmentioning

confidence: 99%

Phospholipid scramblase 1: a protein with multiple functions via multiple molecular interactors

et al. 2022

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Phospholipid scramblase 1 (PLSCR1) is the most studied protein of the scramblase family. Originally, it was identified as a membrane protein involved in maintaining plasma membrane asymmetry. However, studies conducted over the past few years have shown the involvement of PLSCR1 in several other cellular pathways. Indeed, PLSCR1 is not only embedded in the plasma membrane but is also expressed in several intracellular compartments where it interacts with a diverse repertoire of effectors, mediators, and regulators contributing to distinct cellular processes. Although most PLSCR1 interactors are thought to be cell-type specific, PLSCR1 often exerts its regulatory functions through shared mechanisms, including the trafficking of different molecules within intracellular vesicles such as endosomes, liposomes, and phagosomes. Intriguingly, besides endogenous proteins, PLSCR1 was also reported to interact with exogenous viral proteins, thereby regulating viral uptake and spread. This review aims to summarize the current knowledge about the multiple roles of PLSCR1 in distinct cellular pathways.

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“…Based on cell-cluster-markers and TAMs-related-genes, TOP 8 genes (C1QTNF6, CCNB1, FSCN1, HMMR, KPNA2, PRC1, RRM2, and TK1) significantly associated with prognosis were obtained (Figure 2). These have obvious benefits to clinicians for the assessment of patient prognosis (36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49). The same data were used to construct a risk score model containing 9 factors (C1QTNF6, FSCN1, KPNA2, GLI2, TYMS, BIRC3, RBBP7, KRT8, and GPR65) for prognostic evaluation (Figure 2) (50)(51)(52)(53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

Significance of macrophage infiltration in the prognosis of lung adenocarcinoma patients evaluated by scRNA and bulkRNA analysis

Zhu¹,

Zheng²,

Liu³

et al. 2022

Front. Immunol.

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PurposeTo investigate the significance of macrophage infiltration to the prognosis of lung adenocarcinoma.MethodsR language bioinformatics analysis technology, was used to obtain macrophage infiltration-related module genes through WGCNA (Weighted Gene Co-Expression Network Analysis). Marker genes of macrophage subtypes were identified using single-cell sequencing of lung adenocarcinoma tissue. Risk score models were constructed and validated using external data cohorts and clinical samples.ResultsAnalysis of cohorts TCGA-LUAD, GSE11969, GSE31210, GSE50081, GSE72094 and GSE8894, revealed a negative correlation between macrophage infiltration and survival. Immunohistochemical analyses of clinical samples were consistent with these data. Based on cell-cluster-markers and TAMs-related-genes, TOP8 genes were obtained (C1QTNF6, CCNB1, FSCN1, HMMR, KPNA2, PRC1, RRM2, and TK1) with a significant association to prognosis. Risk score models including 9 factors (C1QTNF6, FSCN1, KPNA2, GLI2, TYMS, BIRC3, RBBP7, KRT8, GPR65) for prognosis were constructed. The efficacy, stability and generalizability of the risk score models were validated using multiple data cohorts (GSE19188, GSE26939, GSE31210, GSE50081, GSE42127, and GSE72094).ConclusionsMacrophage infiltration negatively correlates with prognosis in patients with lung adenocarcinoma. Based on cell-cluster-markers and TAMs-related-genes, both TOP8 genes (C1QTNF6, CCNB1, FSCN1, HMMR, KPNA2, PRC1, RRM2, TK1) and risk score models using C1QTNF6, FSCN1, KPNA2, GLI2, TYMS, BIRC3, RBBP7, KRT8, GPR65 could predict disease prognosis.

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Nuclear accumulation of KPNA2 impacts radioresistance through positive regulation of the PLSCR1‐STAT1 loop in lung adenocarcinoma

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 10 publications

References 61 publications

Oxidative stress mediates nucleocytoplasmic shuttling of KPNA2 via AKT1‐CDK1 axis‐regulated S62 phosphorylation

Oxidative stress mediates nucleocytoplasmic shuttling of KPNA2 via AKT1‐CDK1 axis‐regulated S62 phosphorylation

Phospholipid scramblase 1: a protein with multiple functions via multiple molecular interactors

Significance of macrophage infiltration in the prognosis of lung adenocarcinoma patients evaluated by scRNA and bulkRNA analysis

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