Characterization of a small-molecule inhibitor targeting NEMO/IKKβ to suppress colorectal cancer growth

Yu, Zhenlong; Gao, Jian; Zhang, Xiaolei; Peng, Yulin; Wei, Wenlong; Xu, Jianrong; Li, Zhenwei; Wang, Chao; Zhou, Meirong; Tian, Xiangge; Feng, Lei; Huo, Xiaokui; Liu, Min; Ye, Mingliang; Guo, De‐An; Ma, Xiaochi

doi:10.1038/s41392-022-00888-1

Cited by 32 publications

(15 citation statements)

References 54 publications

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“…On the contrary, NEMO/IKKγ inhibition affects the activity of the NF-κB pathway mediated by the IKK complex (canonical pathway), but not the activity of individual IKKα or IKKβ or the non-canonical pathway. Concordantly, a small compound that blocks the binding of NEMO/IKKγ to IKKβ has shown anticancer activity in colorectal cancer tumor xenografts [43]. Considering that ERK5 inhibition or silencing impaired NEMO/IKKγ expression in EC cells and xenograft tumors, we speculate that ERK5 inhibition could be an effective and safe strategy to impair the NF-κB pathway in those cancers where NF-κB acts as a driver, such as EC.…”

Section: Discussionmentioning

confidence: 91%

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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Section: Discussionmentioning

confidence: 91%

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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“…On the contrary, NEMO/IKKγ inhibition affects the activity of the NF-κB pathway mediated by the IKK complex (canonical pathway), but not the activity of individual IKKα or IKKβ or the non-canonical pathway. Concordantly, a small compound that blocks the binding of NEMO/IKKγ to IKKβ has shown anticancer activity in colorectal cancer tumor xenografts [ 50 ]. Considering that ERK5 inhibition or silencing impaired NEMO/IKKγ expression in EC cells and xenograft tumors, we speculate that ERK5 inhibition could be an effective and safe strategy to impair the NF-κB pathway in those cancers where NF-κB acts as a driver, such as EC.…”

Section: Discussionmentioning

confidence: 99%

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

Diéguez-Martínez

Espinosa-Gil

Yoldi

et al. 2022

Cell. Mol. Life Sci.

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Endometrial cancer (EC) is the most common type of gynecologic 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 therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different stressors, including oxidative stress and cytokines. Previous evidence supports a role for the MEK5-ERK5 pathway in the pathology of several cancers. We 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 or silencing decreased EGF-induced EC cell proliferation, and that genetic deletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic inhibition or ERK5 silencing 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, genetic or pharmacologic 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 deletion 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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“…The Surflex-Dock module of Sybyl-X2.1 software (Tripos Associates Inc., S.H.R. ; St. Louis, MO 631444, USA) was used for molecular docking to predict the binding mode of ASD with the Pi3k and AKT based on previous studies ( Yu et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Akebia saponin D protects hippocampal neurogenesis from microglia-mediated inflammation and ameliorates depressive-like behaviors and cognitive impairment in mice through the PI3K-Akt pathway

Liu

Xiao

et al. 2022

Front. Pharmacol.

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Given the ability of akebia saponin D (ASD) to protect various types of stem cells, in the present study, we hypothesized that ASD could promote the proliferation, differentiation, and survival of neural stem/precursor cells (NSPCs), even in a microglia-mediated inflammatory environment, thereby mitigating inflammation-related neuropsychopathology. We established a mouse model of chronic neuroinflammation by exposing animals to low-dose lipopolysaccharide (LPS, 0.25 mg/kg/d) for 14 days. The results showed that chronic exposure to LPS strikingly reduced hippocampal levels of PI3K and pAkt and neurogenesis in mice. In the presen of a microglia-mediated inflammatory niche, the PI3K-Akt signaling in cultured NSPCs was inhibited, promoting their apoptosis and differentiation into astrocytes, while decreasing neurogenesis. Conversely, ASD strongly increased the levels of PI3K and pAkt and stimulated NSPC proliferation, survival and neuronal differentiation in the microglia-mediated inflammatory niche in vitro and in vivo. ASD also restored the synaptic function of hippocampal neurons and ameliorated depressive- and anxiety-like behaviors and cognitive impairment in mice chronically exposed to LPS. The results from network pharmacology analysis showed that the PI3K-AKT pathway is one of the targets of ASD to against major depressive disorder (MDD), anxiety and Alzheimer’s disease (AD). And the results from molecular docking based on computer modeling showed that ASD is bound to the interaction interface of the PI3K and AKT. The PI3K-Akt inhibitor LY294002 blocked the therapeutic effects of ASD in vitro and in vivo. These results suggested that ASD protects NSPCs from the microglia-mediated inflammatory niche, promoting their proliferation, survival and neuronal differentiation, as well as ameliorating depressive- and anxiety-like behaviors and cognitive impairment by activating the PI3K-AKT pathway. Our work suggests the potential of ASD for treating Alzheimer’s disease, depression and other cognitive disorders involving impaired neurogenesis by microglia-mediated inflammation.

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Characterization of a small-molecule inhibitor targeting NEMO/IKKβ to suppress colorectal cancer growth

Cited by 32 publications

References 54 publications

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

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

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

Akebia saponin D protects hippocampal neurogenesis from microglia-mediated inflammation and ameliorates depressive-like behaviors and cognitive impairment in mice through the PI3K-Akt pathway

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