JWA reverses cisplatin resistance via the CK2—XRCC1 pathway in human gastric cancer cells

Xu, Wei; Chen, Qi; Wang, Q; Sun, Youxuan; Wang, S; Li, A; Xu, Shiqin; Røe, Oluf Dimitri; Wang, M; Zhang, R; Yang, Liuqing; Zhou, Jianwei

doi:10.1038/cddis.2014.517

Cited by 48 publications

(64 citation statements)

References 49 publications

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“…In these cells, reduced DNA repair capacity and increased reactive oxygen species (ROS) production have been associated with enhanced cellular sensitivity to cisplatin. Moreover, increased XRCC1 expression has been associated with cisplatin resistance in gastric cancer cells [17, 18]. The thioredoxin like protein-1 (TXNL-1) mediated downregulation of XRCC1 has been shown to be a novel mechanism for cisplatin sensitivity in gastric cancer cells [17].…”

Section: Introductionmentioning

confidence: 99%

Differential role of base excision repair proteins in mediating cisplatin cytotoxicity

et al. 2017

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Interstrand crosslinks (ICLs) are covalent lesions formed by cisplatin. The mechanism for the processing and removal of ICLs by DNA repair proteins involves nucleotide excision repair (NER), homologous recombination (HR) and fanconi anemia (FA) pathways. In this report, we monitored the processing of a flanking uracil adjacent to a cisplatin ICL by the proteins involved in the base excision repair (BER) pathway. Using a combination of extracts, purified proteins, inhibitors, functional assays and cell culture studies, we determined the specific BER proteins required for processing a DNA substrate with a uracil adjacent to a cisplatin ICL. Uracil DNA glycosylase (UNG) is the primary glycosylase responsible for the removal of uracils adjacent to cisplatin ICLs, whereas other uracil glycosylases can process uracils in the context of undamaged DNA. Repair of the uracil adjacent to cisplatin ICLs proceeds through the classical BER pathway, highlighting the importance of specific proteins in this redundant pathway. Removal of uracil is followed by the generation of an abasic site and subsequent cleavage by AP endonuclease 1 (APE1). Inhibition of either the repair or redox domain of APE1 gives rise to cisplatin resistance. Inhibition of the lyase domain of Polymerase β (Polβ) does not influence cisplatin cytotoxicity. In addition, lack of XRCC1 leads to increased DNA damage and results in increased cisplatin cytotoxicity. Our results indicate that BER activation at cisplatin ICLs influences crosslink repair and modulates cisplatin cytotoxicity via specific UNG, APE1 and Polβ polymerase functions.

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Section: Introductionmentioning

confidence: 99%

Differential role of base excision repair proteins in mediating cisplatin cytotoxicity

et al. 2017

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“…JWA enhances the apoptosis of certain chemotherapeutic agents [15–17]. In resectable human GC, JWA is a novel candidate predictive factor and prognostic marker for benefits from adjuvant platinum-based chemotherapy (FLO or FLP) [13].…”

Section: Introductionmentioning

confidence: 99%

JWA down-regulates HER2 expression via c-Cbl and induces lapatinib resistance in human gastric cancer cells

Zhu

Wang

et al. 2016

Oncotarget

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Human epidermal growth factor receptor 2 (HER2) targeted therapy is currently considered as the standard treatment for HER2-positive advanced gastric cancer (GC). However, unsatisfactory results of recent phase III clinical trials involving lapatinib suggested biomarkers for selection of patients. The aim of this study was to identify JWA as a biomarker for lapatinib resistance in GC cells and elucidate the underlying mechanisms. Lapatinib was effective to the intrinsic cisplatin-resistant GC cells. JWA activation conferred lapatinib unresponsiveness, but reversed cisplatin resistance in GC cells. Whereas, deletion of JWA significantly restored lapatinib suppression on proliferation and lapatinib-induced apoptosis. JWA-induced down-regulation of HER2 and activation of ERK phosphorylation led to lapatinib resistance. Furthermore, c-Cbl represented a novel mechanism for HER2 degradation enhanced by JWA in GC cells. Taken together, JWA is a potential predictive marker for lapatinib resistance, targeting the patients that may benefit from lapatinib treatment in human GC.

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“…HGC-27 cells were transfected for 24 h with Flag-JWA using Lipofectamine 2000 as described previously [18]. Cells were lysed in 20 mM Tris (pH 8.0), 137 mM NaCl, 10% glycerol, and 0.2% Triton X-100.…”

Section: Methodsmentioning

confidence: 99%

JWA loss promotes cell migration and cytoskeletal rearrangement by affecting HER2 expression and identifies a high-risk subgroup of HER2-positive gastric carcinoma patients

et al. 2016

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Background and AimsJWA, a microtubule-associated protein (MAP) involved in apoptosis, has been identified as a suppressor of metastasis, and it affects cell migration in melanoma and its downregulation in tumor is an idependent negative prognostic factor in resectable gastric cancer. HER2 overexpression has been observed in gastric cancer (GC) cells and implicated in the metastatic phenotype. However, the biological role of JWA in migration and its clinical value in HER2-positive GC remain elusive.ResultsJWA suppresses EGF-induced cell migration and actin cytoskeletal rearrangement by abrogating HER2 expression and downstream PI3K/AKT signaling in HER2-overexpressing GC cell lines. The modulation of HER2 by JWA is dependent on ERK activation and consequent PEA3 upregulation and activation. Reduced JWA expression is associated with high HER2 expression and with poor survival in patients with AGC, whereas HER2 expression alone is not associated with survival. However, concomitant low JWA and high HER2 expression is associated with unfavorable outcomes. Additionally, when patients were stratified by JWA expression, those with higher HER2 expression in the low JWA expression subgroup exhibited worse survival.MethodsThe impact of JWA on the EGF-induced migration of HER2-positive GC cells was studied using transwell assays and G-LISA assays. Western blotting, real-time PCR, electrophoretic mobility shift assays and luciferase assays were utilized to investigate the mechanisms by which JWA affects HER2. The association of JWA with HER2 and its clinical value were further analyzed by IHC in 128 pairs of advanced gastric cancer (AGC) and adjacent normal tissue samples.ConclusionsThis study characterizes a novel mechanism for regulating cell motility in HER2-overexpressing GC cells involving JWA-mediated MEK/ERK/PEA3 signaling activation and HER2 downregulation. Furthermore, JWA may be a useful prognostic indicator for advanced GC and may help stratify HER2-positive patient subgroups to better identify unfavorable outcomes.

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JWA reverses cisplatin resistance via the CK2—XRCC1 pathway in human gastric cancer cells

Cited by 48 publications

References 49 publications

Differential role of base excision repair proteins in mediating cisplatin cytotoxicity

Differential role of base excision repair proteins in mediating cisplatin cytotoxicity

JWA down-regulates HER2 expression via c-Cbl and induces lapatinib resistance in human gastric cancer cells

JWA loss promotes cell migration and cytoskeletal rearrangement by affecting HER2 expression and identifies a high-risk subgroup of HER2-positive gastric carcinoma patients

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