Inulanolide A as a new dual inhibitor of NFAT1-MDM2 pathway for breast cancer therapy

Qin, Jiang‐Jiang; Wang, Wei; Sarkar, Sushanta; Voruganti, Sukesh; Agarwal, Rajesh; Zhang, Ruiwen

doi:10.18632/oncotarget.8873

Cited by 27 publications

(26 citation statements)

References 36 publications

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“…In many human cancers including sarcomas, breast and others, p53 is now recognized to be the most frequently inactivated gene due to blocking p53-dependent transactivation by extra MDM2 genes [ 25 ]. MDM2 overexpression contributes to cancer initiation, maintenance or progression [ 38 , 39 ], and amplification of MDM2 genes or proteins is usually a feature of many tumors that retain wild-type p53. The clinical studies also indicate that p53 reactivation offers an attractive strategy for cancer therapy [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

The β-glucan fromLentinus edodessuppresses cell proliferation and promotes apoptosis in estrogen receptor positive breast cancers

Zou

2017

Oncotarget

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Breast cancer is now the most common cancer in worldwide women, and novel interventions are needed to overcome the resistance occurring in the estrogen-targeted endocrine therapy. Herein, we demonstrate that the β-glucan from Lentinus edodes (LNT) exhibited a profound inhibition ratio of ∼53% against estrogen receptor positive (ER+) MCF-7 tumor growth in nude mice similar to the positive control of cisplatin. Immunohistochemistry images showed that LNT evidently suppressed cell proliferation and promoted apoptosis in MCF-7 tumor tissues. The Western blotting analysis indicated that LNT up-regulated the tumor suppressor p53, phosphorylated extracellular signal-regulated kinase1/2 (p-ERK1/2), cleaved-Caspase 3 and poly [ADP (ribose)] polymerase 1 (PARP 1) protein levels, and reduced the expression of mouse double minute 2 (MDM2), telomerase reverse transcriptase (TERT), nuclear factor-kappa B (NF-κB) p65, B-cell lymphoma-2 (Bcl-2), estrogen receptor α (ERα), etc. in tumor tissues. Moreover, LNT significantly suppressed phosphatidylinositol 3-kinase (PI3K), phosphorylated protein kinase B (p-Akt) and mammalian target of rapamycin (mTOR) protein levels. It was thus proposed that LNT inhibited MCF-7 tumor growth through suppressing cell proliferation and enhancing apoptosis possibly via multiple pathways such as PI3K/Akt/mTOR, NF-κB-, ERK-, ERα-, caspase- and p53-dependent pathways. Interestingly, the cell viability assay, siRNA transfection, Western blotting and flow cytometric analysis suggested that LNT targeted p53/ERα to only suppress cell proliferation via cell cycle arrest at G2/M phase without apoptosis in vitro. The big difference between in vivo and in vitro data suggested that the immune responses triggered by the polysaccharide should mainly contribute to the apoptotic effect in vivo. Overall, this work provides a novel strategy to treat ER+ breast cancers by using a naturally occurring β-glucan from mushrooms.

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Section: Discussionmentioning

confidence: 99%

The β-glucan fromLentinus edodessuppresses cell proliferation and promotes apoptosis in estrogen receptor positive breast cancers

Zou

2017

Oncotarget

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“…In colorectal cancer cells, USP7 may regulate the deubiquitination of β-catenin, although the detailed binding mechanisms need to be further investigated . Considering that MDM2 and MDMX are highly expressed in prostate, breast, cervical, and colorectal cancer (Cressey et al, 2006;Voruganti et al, 2015;Qin et al, 2016aQin et al, ,b, 2017Stiasny et al, 2017;Wang et al, 2018a), USP7-mediated stabilization of MDM2 and MDMX may also contribute to the progression of these diseases.…”

Section: The Role Of Usp7-mdm2/mdmx-p53 Network In Human Cancer and Imentioning

confidence: 99%

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Cheng

et al. 2020

Front. Cell Dev. Biol.

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The p53 tumor suppressor protein and its major negative regulators MDM2 and MDMX oncoproteins form the MDM2/MDMX-p53 circuitry, which plays critical roles in regulating cancer cell growth, proliferation, cell cycle progression, apoptosis, senescence, angiogenesis, and immune response. Recent studies have shown that the stabilities of p53, MDM2, and MDMX are tightly controlled by the ubiquitinproteasome system. Ubiquitin specific protease 7 (USP7), one of the most studied deubiquitinating enzymes plays a crucial role in protecting MDM2 and MDMX from ubiquitination-mediated proteasomal degradation. USP7 is overexpressed in human cancers and contributes to cancer initiation and progression. USP7 inhibition promotes the degradation of MDM2 and MDMX, activates the p53 signaling, and causes cell cycle arrest and apoptosis, making USP7 a potential target for cancer therapy. Several small-molecule inhibitors of USP7 have been developed and shown promising efficacy in preclinical settings. In the present review, we focus on recent advances in the understanding of the USP7-MDM2/MDMX-p53 network in human cancers as well as the discovery and development of USP7 inhibitors for cancer therapy.

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“…Because the NFAT1-MDM2 signaling pathway has been implicated in prostate cancer cell proliferation and apoptosis ( Li et al, 2005 ; Zhang et al, 2012 ), it was hypothesized that targeting the NFAT1–MDM2 interaction could represent a potential therapeutic strategy for prostate cancer. We have recently discovered a novel dimeric sesquiterpenoid, Inulanolide A (InuA, Figure 1A ), which functions as a dual inhibitor of MDM2 and NFAT1 ( Qin et al, 2016b , 2017b ). InuA is structurally and functionally distinct from the previously reported SMIs of MDM2 and NFAT1 ( Nag et al, 2013 ; Qin et al, 2014 ; Lemos et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Targeting the NFAT1-MDM2-MDMX Network Inhibits the Proliferation and Invasion of Prostate Cancer Cells, Independent of p53 and Androgen

Qin

Wang

et al. 2017

Front. Pharmacol.

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The MDM2 and MDMX oncogenes are overexpressed in various types of human cancer and are highly associated with the initiation, progression, metastasis and chemotherapeutic resistance of these diseases, including prostate cancer. The present study was designed to test a natural MDM2 inhibitor, Inulanolide A (InuA), for anti-prostate cancer activity and to determine the underlying mechanism(s) of action. InuA directly bound to the RING domains of both MDM2 and MDMX with high affinity and specificity and disrupted MDM2-MDMX binding, markedly enhancing MDM2 protein degradation. We further discovered that InuA bound to the DNA binding domain of NFAT1, resulting in marked inhibition of MDM2 transcription. InuA inhibited the proliferation, migration, and invasion of prostate cancer cells, regardless of their p53 status and AR responsiveness. Double knockdown of MDM2 and NFAT1 also revealed that the expression of both of these molecules is important for InuA’s inhibitory effects on the proliferation and invasion of prostate cancer cells. In summary, InuA represents a novel class of bifunctional MDM2 inhibitors, and should be further investigated as a candidate lead compound for prostate cancer prevention and therapy.

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Inulanolide A as a new dual inhibitor of NFAT1-MDM2 pathway for breast cancer therapy

Cited by 27 publications

References 36 publications

The β-glucan fromLentinus edodessuppresses cell proliferation and promotes apoptosis in estrogen receptor positive breast cancers

The β-glucan fromLentinus edodessuppresses cell proliferation and promotes apoptosis in estrogen receptor positive breast cancers

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Targeting the NFAT1-MDM2-MDMX Network Inhibits the Proliferation and Invasion of Prostate Cancer Cells, Independent of p53 and Androgen

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