Reversal of ABCB1-related multidrug resistance by ERK5-IN-1

Wang, Fang; Li, Delan; Zheng, Zongheng; To, Kenneth K.W.; Chen, Zhen; Zhong, Mengjun; Su, Xiaodong; Chen, Likun; Fu, Liwu

doi:10.1186/s13046-020-1537-9

Cited by 22 publications

(15 citation statements)

References 56 publications

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“…Chemotherapy is introduced to breast cancer treatment as neoadjuvant chemotherapy aiming to shrink locally advanced tumors before surgery, as adjuvant chemotherapy after surgical intervention to eliminate residual cancer cells, as well as a treatment option for advanced metastatic breast cancers [ 49 ]. Moreover, inhibition of EGFR signaling is associated with decreased drug efflux activity [ 50 ]. In the case of TNBC, which does not respond to hormonal and targeted therapy, the main line of treatment is chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Complement inhibitor CSMD1 modulates epidermal growth factor receptor oncogenic signaling and sensitizes breast cancer cells to chemotherapy

Gialeli

Tuysuz

Staaf

et al. 2021

J Exp Clin Cancer Res

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Background Human CUB and Sushi multiple domains 1 (CSMD1) is a large membrane-bound tumor suppressor in breast cancer. The current study aimed to elucidate the molecular mechanism underlying the effect of CSMD1 in highly invasive triple negative breast cancer (TNBC). Methods We examined the antitumor action of CSMD1 in three TNBC cell lines overexpressing CSMD1, MDA-MB-231, BT-20 and MDA-MB-486, in vitro using scanning electron microscopy, proteome array, qRT-PCR, immunoblotting, proximity ligation assay, ELISA, co-immunoprecipitation, immunofluorescence, tumorsphere formation assays and flow cytometric analysis. The mRNA expression pattern and clinical relevance of CSMD1 were evaluated in 3520 breast cancers from a modern population-based cohort. Results CSMD1-expressing cells had distinct morphology, with reduced deposition of extracellular matrix components. We found altered expression of several cancer-related molecules, as well as diminished expression of signaling receptors including Epidermal Growth Factor Receptor (EGFR), in CSMD1-expressing cells compared to control cells. A direct interaction of CSMD1 and EGFR was identified, with the EGF-EGFR induced signaling cascade impeded in the presence of CSMD1. Accordingly, we detected increased ubiquitination levels of EGFR upon activation in CSMD1-expressing cells, as well as increased degradation kinetics and chemosensitivity. Accordingly, CSMD1 expression rendered tumorspheres pretreated with gefitinib more sensitive to chemotherapy. In addition, higher mRNA levels of CSMD1 tend to be associated with better outcome of triple negative breast cancer patients treated with chemotherapy. Conclusions Our results indicate that CSMD1 cross-talks with the EGFR endosomal trafficking cascade in a way that renders highly invasive breast cancer cells sensitive to chemotherapy. Our study unravels one possible underlying molecular mechanism of CSMD1 tumor suppressor function and may provide novel avenues for design of better treatment.

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Section: Discussionmentioning

confidence: 99%

Complement inhibitor CSMD1 modulates epidermal growth factor receptor oncogenic signaling and sensitizes breast cancer cells to chemotherapy

Gialeli

Tuysuz

Staaf

et al. 2021

J Exp Clin Cancer Res

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“…Furthermore, ERK5 silencing also potentiates doxorubicin and cisplatin therapies in malignant mesothelioma cells [48], or doxorubicin, cyclophosphamide, and paclitaxel in TNBC cells [49]. The mechanism by which ERK5 inhibition sensitizes several types of cancer cells remains to be described, although it has been suggested that it could be due to inhibition of some of the ABC transporters [50]. Since we found that pharmacologic inhibition of the NF-κB pathway (IKKβ inhibitor BAY-117082) also potentiated the cytotoxic effect of paclitaxel and carboplatin in EC cells, it is plausible that NF-κB inhibition may mediate the sensitization of EC cells to chemotherapy exerted by ERK5 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

Diéguez-Martínez

Espinosa-Gil

Yoldi

et al. 2022

Preprint

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Endometrial cancer (EC) is the most common type of gynaecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel molecular therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different forms of stress, including oxidative stress and cytokines. Previous evidence support a role for the MEK5-ERK5 pathway in the pathology of several cancers. We have investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed alterations in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition decreased EGF-induced EC cell proliferation, and that depletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic or genetic silencing of ERK5 impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, impairment of ERK5 resulted in downregulation of NEMO/IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 depletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell proliferation and survival. We propose the ERK5/NF-κB axis as new target for EC treatment.

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“…Animal study was performed as previously described [ 44 , 45 ]. The BACB/C nude mice xenograft models were used for the in vivo study.…”

Section: Methodsmentioning

confidence: 99%

Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation

Zou

Zeng

et al. 2021

Biomedicines

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The overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) subfamily B member 1 (ABCB1; P-glycoprotein; MDR1) in some types of cancer cells is one of the mechanisms responsible for the development of multidrug resistance (MDR), which leads to the failure of chemotherapy. Therefore, it is important to inhibit the activity or reduce the expression level of ABCB1 to maintain an effective intracellular level of chemotherapeutic drugs. In this study, we found that rutaecarpine, a bioactive alkaloid isolated from Evodia Rutaecarpa, has the capacity to reverse ABCB1-mediated MDR. Our data indicated that the reversal effect of rutaecarpine was related to the attenuation of the protein level of ABCB1. Mechanistically, we demonstrated that ABCB1 is a newly discovered substrate of E3 ubiquitin ligase membrane-associated RING-CH 8 (MARCH8). MARCH8 can interact with ABCB1 and promote its ubiquitination and degradation. In short, rutaecarpine increased the degradation of ABCB1 protein by upregulating the protein level of MARCH8, thereby antagonizing ABCB1-mediated MDR. Notably, the treatment of rutaecarpine combined with other anticancer drugs exhibits a therapeutic effect on transplanted tumors. Therefore, our study provides a potential chemotherapeutic strategy of co-administrating rutaecarpine with other conventional chemotherapeutic agents to overcome MDR and improve therapeutic effect.

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Reversal of ABCB1-related multidrug resistance by ERK5-IN-1

Cited by 22 publications

References 56 publications

Complement inhibitor CSMD1 modulates epidermal growth factor receptor oncogenic signaling and sensitizes breast cancer cells to chemotherapy

Complement inhibitor CSMD1 modulates epidermal growth factor receptor oncogenic signaling and sensitizes breast cancer cells to chemotherapy

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation

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