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

Ma, Ling; Zhu, Weiyou; Wang, Qiang; Yang, Fengming; Qian, Ji; Xu, Tongpeng; Wang, Shouyu; Zhou, Jianwei; Shu, Yongqian

doi:10.18632/oncotarget.12374

Cited by 10 publications

(18 citation statements)

References 30 publications

(34 reference statements)

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“…Previous studies have reported that the HER family receptors are degraded with a help of their specific ubiquitin ligases [21] , [22] . For example, HER1 is degraded by ubiquitin ligase c-Cbl [23] , HER2 is mediated by c-Cbl [24] , [25] , [26] or chaperon-interacting protein (CHIP) [27] , [28] . HER4 is ubiquitinated by WWP1 [32] or Itch [33] .…”

Section: Introductionmentioning

confidence: 99%

Estradiol promotes rapid degradation of HER3 in ER-positive breast cancer cell line MCF-7

Suga

Izumiyama

Tanaka

2018

Biochemistry and Biophysics Reports

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HER3, a member of the receptor tyrosine kinase super family, is overexpressed in a number of cancers, and is associated with malignant phenotypes. Control of the protein stability of the membrane, as well as nuclear receptors, has been known to be an important process affecting tumor cells; however, their relationships have yet to be elucidated. In this study, we demonstrate that estradiol promotes rapid degradation of HER3 via the proteasome pathway in ER-positive breast cancer, MCF-7. ER prevented HER3 degradation, and knockdown of ER expression by si-RNA promoted rapid degradation of HER3. Breakdown of HER3 and ER were regulated by a ubiquitin ligase Nedd4-1 in the presence of estradiol stimulation. We speculate that estradiol quickly degrades ER, making HER3 accessible by Nedd4-1, and leads to the rapid degradation of HER3. In addition, knockdown of ubiquitin ligase Nedd4-1 enhances estradiol induced cell proliferation. These results indicate that HER3 and Nedd4-1 in ER-positive breast cancers might be an important therapeutic target.

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Section: Introductionmentioning

confidence: 99%

Estradiol promotes rapid degradation of HER3 in ER-positive breast cancer cell line MCF-7

Suga

Izumiyama

Tanaka

2018

Biochemistry and Biophysics Reports

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“…Our previous study reported that JWA (adenosine diphophate-ribosylation-like factor 6 interacting protein 5, ARL6ip5) reversed cisplatin resistance in human GC 59 , whereas lower expression of JWA sensitized cisplatinresistant GC cells to lapatinib-induced apoptosis 32 . Collectively, these three studies have led to the proposals for some significant therapy regimens in GC patients: higher expression of JWA may be used as a biomarker for cisplatin treatment, lower expression of JWA may be utilized to identify patients that would benefit from HER2targeted therapy; in terms of the anti-angiogenesis therapy, silencing of circRACGAP1 may be a potential intervention strategy to reduce the toxicities and promote the antitumor effect of apatinib.…”

Section: Discussionmentioning

confidence: 99%

“…Western blotting and immunohistochemical staining were performed as previously described 32 . The antibodies used were as follows: monoclonal anti-GAPDH (loading control) (1:1000, Beyotime, Haimen, Jiangsu, China) and monoclonal anti-LC3B, SQSTM1, ATG7, and VEGFR-2 (1: 1000, Cell Signaling Technology, Danvers, MA, USA).…”

Section: Western Blotting Immunohistochemical Staining and Antibodiesmentioning

confidence: 99%

Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7

Wang

Xie

et al. 2020

Cell Death Dis

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The positive results of the apatinib phase III trial have cast new light on treatment for patients with advanced gastric cancer (GC). However, in terms of safety, apatinib toxicities may lead to a dose modification or treatment interruption. Therefore, proper intervention is urgently needed to help patients benefit from apatinib treatment. In this study, we found that apatinib promoted autophagy activation via upregulation of ATG7 expression and autophagy inhibition enhanced apatinib-induced apoptosis. With microRNA and circular RNA-sequencing analyses of GC xenograft models, we demonstrated that circRACGAP1 functioned as an endogenous sponge for miR-3657 to inhibit its activity and further upregulate ATG7 expression. Silencing of circRACGAP1 inhibited apatinib-induced autophagy, which was rescued by miR-3657. Moreover, knockdown of circRACGAP1 sensitized GC cells to apatinib via autophagy inhibition in vitro and in vivo. These findings provided the first evidence that the circRACGAP1-miR-3657-ATG7 axis mediates a novel regulatory pathway critical for the regulation of apatinib sensitivity in GC. Thus, specific blockage of circRACGAP1 may be a potential therapeutic strategy to reduce the toxicities of apatinib and enhance its therapeutic effect in human GC.

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“…Patients with lower expression of JWA in tumor tissues usually suffer worse survival than those with higher expression [15,16]. JWA negatively regulates HER2 expression and inhibits cell proliferation and migration in human GC cells through transcription and ubiquitination related mechanisms [17,18]. However, the role of JWA in regulating HER2 expression and its underlying mechanism in BC have not been determined.…”

Section: Introductionmentioning

confidence: 99%

The Agonist of JWA Gene JAC1 Suppresses Proliferation of Breast Cancer Through the JWA/p38/SMURF1/HER2 Signaling

Ren

Chen²,

Chen

et al. 2020

Preprint

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Background The overexpression of HER2 is associated with malignant proliferation and invasiveness in breast cancer. Although HER2-targeting drugs have been clinically applied for cancer treatment, none of them could reduce overexpressed HER2. In this study, we reported that JAC1 could suppress proliferation of breast cancer cells via degrading HER2. Methods JWA-HER2 association was analyzed by IHC in 90 paired cases of breast cancer and adjacent non-cancerous tissues. Regulatory effect of JAC1, the agonist of JWA gene, on HER2-positive breast cancer cells was studied using colony formation assay. The effect of JAC1 on the localization of HER2 was detected by immunofluorescence microscopy assay. Western blotting, RT-PCR and immunoprecipitation assay were utilized to investigate the mechanisms of JWA on regulating HER2. Finally, xenograft mouse models were established in nude mice using BT474 cells to confirm the effect of JAC1 in vivo. Results JAC1, a small molecule agonist of JWA gene, dose-dependently suppressed proliferation in HER2-positive breast cancer in vitro and in vivo through degrading HER2. The mechanistic evidences showed that JAC1 increased the ubiquitination of HER2 at the K716 through the E3 ubiquitin ligase SMURF1. Furthermore, SMURF1 was activated due to reduced expression of NEDD4, an E3 ubiquitin ligase for SMURF1 through the JWA-p38-GATA-1-NEDD4 axis. Conclusions JAC1 suppresses the proliferation in HER2-positive breast cancer through the JWA/p38/GATA-1/NEDD4/SMURF1/HER2 signaling. JAC1 may serve as a novel therapeutic agent to breast cancer.

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

Cited by 10 publications

References 30 publications

Estradiol promotes rapid degradation of HER3 in ER-positive breast cancer cell line MCF-7

Estradiol promotes rapid degradation of HER3 in ER-positive breast cancer cell line MCF-7

Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7

The Agonist of JWA Gene JAC1 Suppresses Proliferation of Breast Cancer Through the JWA/p38/SMURF1/HER2 Signaling

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