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. 

/pdf/the-erk5-nf-kb-signaling-pathway-targets-endometrial-cancer-1mqeuw0x.pdf

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

Gastrointestinal cancers are a group of cancers occurred in gastrointestinal tissues with high morbidity and mortality rate. Although numerous studies were conducted on the investigation of gastrointestinal cancers, the real mechanisms haven't been discovered, and no effective methods of prevention and treatment of gastrointestinal cancers have been developed. Autophagy, a vital catabolic process in organisms, have been proven to participate in various mechanisms and signaling pathways, thus producing a regulatory effect on various diseases. The role of autophagy in gastrointestinal cancers remains unclear due to its high complexity. In this review, firstly, the biological features of autophagy will be introduced. Secondly, the role of autophagy in three popular gastrointestinal cancers, namely esophageal cancer, gastric cancer, and colorectal cancer will be described and discussed by reviewing the related literature. We aimed to bring novel insights in exploring the real mechanisms for gastrointestinal cancers and developing effective and efficient therapeutic methods to treat gastrointestinal cancers. 

/pdf/autophagy-in-gastrointestinal-cancers-fwlnblj7.pdf

Autophagy in gastrointestinal cancers

ABSTRACT The mitogen-activated protein kinase kinase 5 (MEK5)/extracellular signal-regulated kinase 5 (ERK5) axis has been reported to promote tumorigenesis in breast cancer (BC). Therefore, targeting the MEK5/ERK5 axis is a potential strategy against BC. BAY-885 is a novel inhibitor of ERK5; however, to date, its anti-tumor effects in BC have not been investigated. This study aimed to assess the anti-tumor effects of BAY-885 in BC and identify its underlying mechanisms of action. Unlike other ERK5 inhibitors, which frequently failed to mimic ERK5 genetic ablation phenotypes, the BAY-885 treatment effectively recapitulated ERK5 depletion effects in BC cells. Results revealed that BAY-885 affected the viability and induced apoptosis in BC cells. Moreover, the BAY-885-mediated downregulation of myeloid cell leukemia-1 (Mcl-1) and upregulation of Bim were dependent on ERK5 inhibition. Furthermore, BAY-885 triggered activation of endoplasmic reticulum (ER) stress, which further led to the upregulation of Bim and downregulation of Mcl-1. ER stress was induced in an ERK5 inhibition-dependent manner. These findings suggested that BAY-885 induced apoptosis in BC cells via ER stress/Mcl-1/Bim axis, suggesting that BAY-885 may serve as a therapeutic agent for BC. GRAPHICAL ABSTRACT

https://www.tandfonline.com/doi/pdf/10.1080/21655979.2022.2078557?needAccess=true

BAY-885, a mitogen-activated protein kinase kinase 5 inhibitor, induces apoptosis by regulating the endoplasmic reticulum stress/Mcl-1/Bim pathway in breast cancer cells

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/2211-5463.13461

Ulinastatin promotes macrophage efferocytosis and ameliorates lung inflammation via the ERK5/Mer signaling pathway

Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors in the world. Although the current treatment methods for HCC are gradually increasing, its efficacy still cannot meet the medical needs of patients with liver cancer, and new and effective treatment strategies are urgently needed. The total flavonoids of Oldenlandia diffusa (FOD) are the main active components in Oldenlandia diffusa, which have anti-inflammatory, antioxidant and anti-tumor effects, but their mechanism of action in liver cancer is unclear. In this study, we examined the effect of FOD on HCC. Using both in vitro and in vivo models, we confirmed that FOD inhibited HCC proliferation and induced apoptosis and autophagy. Mechanistic studies have shown that FOD induces apoptosis and activates autophagy in HCC cells by inducing endoplasmic reticulum stress (ER stress) and activating the PERK-eIF2α-ATF4 signaling pathway. Taken together, our results suggest that FOD is a potential anticancer drug targeting ER stress for the treatment of HCC.

/pdf/total-flavonoids-of-oldenlandia-diffusa-willd-roxb-3a3fjtid.pdf

Total flavonoids of Oldenlandia diffusa (Willd.) Roxb. suppresses the growth of hepatocellular carcinoma through endoplasmic reticulum stress-mediated autophagy and apoptosis

Autophagy is a highly conserved intracellular process that preserves cellular homeostasis by mediating the lysosomal degradation of virtually any component of the cytoplasm. Autophagy is a key instrument of cellular response to several stresses, including endoplasmic reticulum (ER) stress. Cancer cells have developed high dependency on autophagy to overcome the hostile tumor microenvironment. Thus, pharmacological activation or inhibition of autophagy is emerging as a novel antitumor strategy. ERK5 is a novel member of the MAP kinase family that is activated in response to growth factors and different forms of stress. Recent work has pointed ERK5 as a major player controlling cancer cell proliferation and survival. Therefore small-molecule inhibitors of ERK5 have shown promising therapeutic potential in different cancer models. Here, we report for the first time ERK5 as a negative regulator of autophagy. Thus, ERK5 inhibition or silencing induced autophagy in a panel of human cancer cell lines with different mutation patterns. As reported previously, ERK5 inhibitors (ERK5i) induced apoptotic cancer cell death. Importantly, we found that autophagy mediates the cytotoxic effect of ERK5i, since ATG5-/- autophagy-deficient cells viability was not affected by these compounds. Mechanistically, ERK5i stimulated autophagic flux independently of the canonical regulators AMPK or mTORC1. Moreover, ERK5 inhibition resulted in ER stress and activation of the Unfolded Protein Response (UPR) pathways. Specifically, ERK5i induced expression of the ER luminal chaperone BiP (a hallmark of ER stress), the UPR markers CHOP and ATF4, and the spliced form of XBP1. Pharmacological inhibition of UPR with chemical chaperone TUDC, or ATF4 silencing, resulted in impaired ERK5i-mediated UPR, autophagy and cytotoxicity. Overall, our results suggest that ERK5 inhibition induces autophagy-mediated cancer cell death by activating ER stress. Since ERK5 inhibition sensitizes cancer cells and tumors to chemotherapy, future work will determine the relevance of UPR and autophagy in the combined use of chemotherapy and ERK5i to tackle Cancer.

Andrés Gámez-García

Papers

ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress.