ERK signaling promotes IKKε expression and oncogenic functions in pancreatic cancer cells in association with TBK1
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ABSTRACT:
PROVIDER: PRJNA1224495 | ENA |
REPOSITORIES: ENA
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Project description:A variety of cancers utilize RAS-regulated signaling pathways to promote oncogenic phenotypes. A widely studied example is pancreatic cancer, where mutant KRAS signaling leads to activation of MEK/ERK kinases and downstream signaling which promotes oncogenic mechanisms, including cell proliferation. Importantly, ERK inhibitors have shown efficacy in some cancer clinical trials. Previously, others have studied the effects of the related kinases TBK1 and IKKε in pancreatic cancer where they have been shown to promote cell survival. Here, we show that RAS/MAPK signaling promotes expression of IKKε through control of protein stability and not through control of RNA levels. RNAseq analysis indicate that TBK1 and IKKε contribute to the expression of a subset of ERK-regulated genes. Potentially related to the effects on IKKε, proteomic analysis reveals that ERK functions to stabilize a relatively large set of proteins independent of RNA regulation. Knockdown of IKKε and TBK1 individually does not affect growth of MIA PaCa-2 pancreatic cancer cells, but dual knockdown significantly inhibits MIA PaCa-2 growth which is mediated through cell death. Concurrent silencing or inhibition of both TBK1 and IKKε also reduces tumor sphere growth in MIA PaCa-2 cells, correlating with a loss of stemness pathways found with RNAseq. The data suggest the importance of regulation of IKKε by ERK in pancreatic cancer cells and of the combined oncogenic activity of TBK1 and IKKε.
2025-08-05 | PXD060883 | Pride
Project description:A variety of cancers utilize RAS-regulated signaling pathways to promote oncogenic phenotypes. A widely studied example is pancreatic cancer, where mutant KRAS signaling leads to activation of MEK/ERK kinases and downstream signaling which promotes oncogenic mechanisms, including cell proliferation. Importantly, ERK inhibitors have shown efficacy in some cancer clinical trials. Previously, others have studied the effects of the related kinases TBK1 and IKKε in pancreatic cancer where they have been shown to promote cell survival. Here, we show that RAS/MAPK signaling promotes expression of IKKε through control of protein stability and not through control of RNA levels. RNAseq analysis indicate that TBK1 and IKKε contribute to the expression of a subset of ERK-regulated genes. Potentially related to the effects on IKKε, proteomic analysis reveals that ERK functions to stabilize a relatively large set of proteins independent of RNA regulation. Knockdown of IKKε and TBK1 individually does not affect growth of MIA PaCa-2 pancreatic cancer cells, but dual knockdown significantly inhibits MIA PaCa-2 growth which is mediated through cell death. Concurrent silencing or inhibition of both TBK1 and IKKε also reduces tumor sphere growth in MIA PaCa-2 cells, correlating with a loss of stemness pathways found with RNAseq. The data suggest the importance of regulation of IKKε by ERK in pancreatic cancer cells and of the combined oncogenic activity of TBK1 and IKKε.
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Project description:The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF- B anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. This SuperSeries is composed of the following subset Series:; GSE17643: Profiling of immortalized human lung epithelial cells following oncogenic KRAS expression and TBK1 suppression; GSE17671: Profiling of immortalized human lung epithelial cells following infection with oncogenic KRAS (G12V) Experiment Overall Design: Refer to individual Series
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Project description:Non-small-cell lung cancer (NSCLC) is a highly lethal tumor that often develops resistance to targeted therapy. It is shown that Tank-binding kinase 1 (TBK1) phosphorylates AGO2 at S417 (pS417-AGO2), which promotes NSCLC progression by increasing the formation of microRNA-induced silencing complex (miRISC). High levels of pS417-AGO2 in clinical NSCLC specimens are positively associated with poor prognosis. Interestingly, the treatment with EGFR inhibitor Gefitinib can significantly induce pS417-AGO2, thereby increasing the formation and activity of oncogenic miRISC, which may contribute to NSCLC resistance to Gefitinib. Based on these, two therapeutic strategies is developed. One is jointly to antagonize multiple oncogenic miRNAs highly expressed in NSCLC and use TBK1 inhibitor Amlexanox reducing the formation of oncogenic miRISC. Another approach is to combine Gefitinib with Amlexanox to inhibit the progression of Gefitinib-resistant NSCLC. This findings reveal a novel mechanism of oncogenic miRISC regulation by TBK1-mediated pS417-AGO2 and suggest potential therapeutic approaches for NSCLC.
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Project description:The purpose of the dataset is to analyze expression of genes induced by KRAS and regulated by TBK1 The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF- B anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer.
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Project description:The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF- B anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. This SuperSeries is composed of the SubSeries listed below.
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