ERK inhibition in glioblastoma is associated with autophagy activation and tumorigenesis suppression

Stem cells may be a novel treatment modality for organ ischemia, possibly through beneficial paracrine mechanisms. Stem cells from older hosts have been shown to exhibit decreased function during stress. We therefore hypothesized that 1) neonatal bone marrow mesenchymal stem cells (nBMSCs) would produce different levels of IL-6, VEGF, and IGF-1 compared with adults (aBMSCs) when stimulated with TNF or LPS; 2) differences in cytokines would be due to distinct cellular characteristics, such as proliferation or pluripotent potential; and 3) differences in cytokines would be associated with differences in p38 MAPK and ERK signaling within nBMSCs. BMSCs were isolated from adult and neonatal mice. Cells were exposed to TNF or LPS with or without p38 or ERK inhibition. Growth factors were measured via ELISA, proliferation via daily cell counts, cell surface markers via flow cytometry, and pluripotent potential via alkaline phosphatase activity. nBMSCs produced lower levels of IL-6 and VEGF, but higher levels of IGF-1 under basal conditions, as well as after stimulation with TNF, but not LPS. Neonatal and adult BMSCs had similar pluripotent potentials and cell surface markers, but nBMSCs proliferated faster. Furthermore, p38 and ERK appeared to play a more substantial role in nBMSC cytokine and growth factor production. Neonatal stem cells may aid in decreasing the local inflammatory response during ischemia, and could possibly be expanded more rapidly than adult cells prior to therapeutic use.

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Activation of the MAPK pathway mediates resistance to PI3K inhibitors in chronic lymphocytic leukemia (cll)

Blood ◽

10.1182/blood.2020006765 ◽

2021 ◽

Author(s):

Ishwarya Murali ◽

Siddha Kasar ◽

Aishath Naeem ◽

Svitlana Tyekucheva ◽

Jasneet Kaur Khalsa ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Mapk Pathway ◽

Cell Receptor ◽

Lymphocytic Leukemia ◽

Erk Activation ◽

Activating Mutations ◽

Erk Phosphorylation ◽

Whole Exome ◽

Erk Inhibition

Inhibitors of Bruton's tyrosine kinase (BTKi) and phosphatidylinositol 3-kinase delta (PI3Kδi) that target the B cell receptor (BCR) signaling pathway have revolutionized the treatment of chronic lymphocytic leukemia (CLL). While mutations associated with resistance to BTK inhibitors have been identified, limited data are available on mechanisms of resistance to PI3Kδi. Here we present findings from longitudinal whole-exome sequencing of multiply relapsed CLL patients (Ncases=28) enrolled in PI3Ki trials. The non-responder subgroup was characterized by baseline activating mutations in MAP2K1, BRAF and KRAS in 60% of patients. PI3Kδ inhibition failed to inhibit ERK phosphorylation (pERK) in non-responder CLL cells with and without mutations, while treatment with MEKi rescued ERK inhibition. Overexpression of MAP2K1 mutants in vitro led to increased basal and inducible pERK and resistance to idelalisib. These data demonstrate that MAPK/ERK activation plays a key role in resistance to PI3Kδi in CLL and provide rationale for combination therapy with PI3Kδ and ERK inhibitors.

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ERK inhibition represses gefitinib resistance in non-small cell lung cancer cells

Oncotarget ◽

10.18632/oncotarget.24147 ◽

2018 ◽

Vol 9 (15) ◽

pp. 12020-12034 ◽

Cited By ~ 11

Author(s):

Mengfan Qi ◽

Ye Tian ◽

Wang Li ◽

Dan Li ◽

Tian Zhao ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lung Cancer ◽

Small Cell ◽

Lung Cancer Cells ◽

Small Cell Lung ◽

Erk Inhibition ◽

Gefitinib Resistance

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Spatial Regulation of Reactive Oxygen Species via G6PD in Brown Adipocytes Supports Thermogenic Function

10.2337/figshare.16556181 ◽

2021 ◽

Author(s):

Jee Hyung Sohn ◽

Yul Ji ◽

Chang-Yun Cho ◽

Hahn Nahmgoong ◽

Sangsoo Lim ◽

...

Keyword(s):

Gene Expression ◽

Reactive Oxygen Species ◽

Reactive Oxygen ◽

Oxygen Species ◽

Redox Potentials ◽

Brown Adipocytes ◽

Erk Activation ◽

Brown Adipose ◽

Erk Inhibition ◽

Glucose 6 Phosphate Dehydrogenase

Reactive oxygen species (ROS) are associated with various roles of brown adipocytes. Glucose-6-phosphate dehydrogenase (G6PD) controls cellular redox potentials by producing NADPH. Although G6PD upregulates cellular ROS levels in white adipocytes, the roles of G6PD in brown adipocytes remain elusive. Here, we found that G6PD defect in brown adipocytes impaired thermogenic function through excessive cytosolic ROS accumulation. Upon cold exposure, G6PD-deficient mutant (G6PDmut) mice exhibited cold intolerance and downregulated thermogenic gene expression in brown adipose tissue (BAT). In addition, G6PD-deficient brown adipocytes had increased cytosolic ROS levels, leading to ERK activation. In BAT of G6PDmut mice, administration of antioxidant restored the thermogenic activity by potentiating thermogenic gene expression and relieving ERK activation. Consistently, body temperature and thermogenic execution were rescued by ERK inhibition in cold-exposed G6PDmut mice. Taken together, these data suggest that G6PD in brown adipocytes would protect against cytosolic oxidative stress, leading to cold-induced thermogenesis.

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Metabolic Reprogramming by Dual AKT/ERK Inhibition through Imipridones Elicits Unique Vulnerabilities in Glioblastoma

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-18-1040 ◽

2018 ◽

Vol 24 (21) ◽

pp. 5392-5406 ◽

Cited By ~ 16

Author(s):

Chiaki T. Ishida ◽

Yiru Zhang ◽

Elena Bianchetti ◽

Chang Shu ◽

Trang T.T. Nguyen ◽

...

Keyword(s):

Metabolic Reprogramming ◽

Erk Inhibition

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Modulating cell state to enhance suspension expansion of human pluripotent stem cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1714099115 ◽

2018 ◽

Vol 115 (25) ◽

pp. 6369-6374 ◽

Cited By ~ 12

Author(s):

Yonatan Y. Lipsitz ◽

Curtis Woodford ◽

Ting Yin ◽

Jacob H. Hanna ◽

Peter W. Zandstra

Keyword(s):

Stem Cells ◽

Pluripotent Stem Cells ◽

Large Scale ◽

Cell Types ◽

Human Pluripotent Stem Cells ◽

The Body ◽

Altered Expression ◽

Pancreatic Progenitors ◽

Erk Inhibition

The development of cell-based therapies to replace missing or damaged tissues within the body or generate cells with a unique biological activity requires a reliable and accessible source of cells. Human pluripotent stem cells (hPSC) have emerged as a strong candidate cell source capable of extended propagation in vitro and differentiation to clinically relevant cell types. However, the application of hPSC in cell-based therapies requires overcoming yield limitations in large-scale hPSC manufacturing. We explored methods to convert hPSC to alternative states of pluripotency with advantageous bioprocessing properties, identifying a suspension-based small-molecule and cytokine combination that supports increased single-cell survival efficiency, faster growth rates, higher densities, and greater expansion than control hPSC cultures. ERK inhibition was found to be essential for conversion to this altered state, but once converted, ERK inhibition led to a loss of pluripotent phenotype in suspension. The resulting suspension medium formulation enabled hPSC suspension yields 5.7 ± 0.2-fold greater than conventional hPSC in 6 d, for at least five passages. Treated cells remained pluripotent, karyotypically normal, and capable of differentiating into all germ layers. Treated cells could also be integrated into directed differentiated strategies as demonstrated by the generation of pancreatic progenitors (NKX6.1+/PDX1+ cells). Enhanced suspension-yield hPSC displayed higher oxidative metabolism and altered expression of adhesion-related genes. The enhanced bioprocess properties of this alternative pluripotent state provide a strategy to overcome cell manufacturing limitations of hPSC.

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Combined SHP2 and ERK inhibition for the treatment of KRAS-driven Pancreatic Ductal Adenocarcinoma

10.1101/2021.12.14.472574 ◽

2021 ◽

Author(s):

Katrin J Ciecielski ◽

Antonio Mulero-Sanchez ◽

Alexandra Berninger ◽

Laura Ruiz Canas ◽

Astrid Bosma ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Tumor Regression ◽

Mapk Pathway ◽

Single Agent ◽

Ductal Adenocarcinoma ◽

Good Tolerability ◽

Recent Emergence ◽

Erk Inhibition

Mutant KRAS is present in over 90% of pancreatic as well as 30-40% of lung and colorectal cancers and is one of the most common oncogenic drivers. Despite decades of research and the recent emergence of isoform-specific KRASG12C-inhibitors, most mutant KRAS isoforms, including the ones frequently associated with pancreatic ductal adenocarcinoma (PDAC), cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive mechanisms leading to tumor recurrence or resistance. We report here on the combined inhibition of SHP2, a non-receptor tyrosine phosphatase upstream of KRAS, and ERK, a serine/threonine kinase and a key molecule downstream of KRAS in PDAC. This combination shows synergistic anticancer activity in vitro, superior disruption of the MAPK pathway, and significantly increased apoptosis induction compared to single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination. Concurrent inhibition of SHP2 and ERK induces significant tumor regression in multiple PDAC mouse models. Finally, we show evidence that 18F-FDG PET scans can be used to detect and predict early drug responses in animal models. Based on these compelling results, we will investigate this drug combination in a clinical trial (SHERPA, SHP2 and ERK inhibition in pancreatic cancer, NCT04916236), enrolling patients with KRAS-mutant PDAC.

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Inhibition of PI3K/Akt and ERK signaling decreases visfatin-induced invasion in liver cancer cells

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2021-0011 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Candace Miethe ◽

Linda Torres ◽

Megan Zamora ◽

Ramona S. Price

Keyword(s):

Liver Cancer ◽

Cancer Cells ◽

Signaling Pathways ◽

Fatty Acid Synthase ◽

Erk Signaling ◽

Ros Production ◽

Nicotinamide Phosphoribosyltransferase ◽

Liver Cancer Cells ◽

Phosphorylated Akt ◽

Erk Inhibition

Abstract Objectives Visfatin is found in adipose tissue and is referred to as nicotinamide phosphoribosyltransferase (Nampt). Visfatin has anti-apoptotic, proliferative, and metastatic properties and may mediate its effects via ERK and PI3K/Akt signaling. Studies have yet to determine whether inhibition of kinase signaling will suppress visfatin-induced liver cancer. The purpose of this study was to determine which signaling pathways visfatin may promote liver cancer progression. Methods HepG2 and SNU-449 liver cancer cells were exposed to visfatin with or without ERK or PI3K/Akt inhibitor, or both inhibitors combined. These processes that were assessed: proliferation, reactive oxygen species (ROS), lipogenesis, invasion, and matrix metalloproteinase (MMP). Results Inhibition of PI3K/Akt and combination of inhibitors suppressed visfatin-induced viability. ERK inhibition in HepG2 cells decreased visfatin-induced proliferation. ERK inhibitor alone or in combination with PI3K inhibitors effectively suppressed MMP-9 secretion and invasion in liver cancer cells. PI3K and ERK inhibition and PI3K inhibition alone blocked visfatin’s ROS production in SNU-449 cells. These results corresponded with a decrease in phosphorylated Akt and ERK, β-catenin, and fatty acid synthase. Conclusions Akt and ERK inhibition differentially regulated physiological changes in liver cancer cells. Inhibition of Akt and ERK signaling pathways suppressed visfatin-induced invasion, viability, MMP-9 activation, and ROS production.

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