Browse
Submit Data
Databases
API
Help

Dataset Information

26 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcriptional regulation of autophagy in RAS-driven cancers.

ABSTRACT: RAS-driven cancers exhibit variable dependency on autophagy for survival; however, it is not fully understood how. In this issue of the JCI, Cheong and colleagues demonstrate that RAS-dependent elevation of casein kinase 1? (CK1?) negatively regulates autophagy at the level of autophagy gene transcription. Moreover, combined inhibition of both CK1? and autophagy reduced proliferation of RAS-driven tumors. The results of this study provide insight into the connection between mutant RAS and autophagy, and suggest targeting CK1? as a potential therapeutic strategy to modulate autophagy in RAS-driven cancers.

SUBMITTER: Amaravadi RK

PROVIDER: S-EPMC4409024 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Transcriptional regulation of autophagy in RAS-driven cancers.

Amaravadi Ravi K RK

The Journal of clinical investigation 20150323 4

RAS-driven cancers exhibit variable dependency on autophagy for survival; however, it is not fully understood how. In this issue of the JCI, Cheong and colleagues demonstrate that RAS-dependent elevation of casein kinase 1α (CK1α) negatively regulates autophagy at the level of autophagy gene transcription. Moreover, combined inhibition of both CK1α and autophagy reduced proliferation of RAS-driven tumors. The results of this study provide insight into the connection between mutant RAS and autoph ...[more]

PMID: 25798614

Similar Datasets

Casein kinase 1?-dependent feedback loop controls autophagy in RAS-driven cancers.

Project description:Activating mutations in the RAS oncogene are common in cancer but are difficult to therapeutically target. RAS activation promotes autophagy, a highly regulated catabolic process that metabolically buffers cells in response to diverse stresses. Here we report that casein kinase 1? (CK1?), a ubiquitously expressed serine/threonine kinase, is a key negative regulator of oncogenic RAS-induced autophagy. Depletion or pharmacologic inhibition of CK1? enhanced autophagic flux in oncogenic RAS-driven human fibroblasts and multiple cancer cell lines. FOXO3A, a master longevity mediator that transcriptionally regulates diverse autophagy genes, was a critical target of CK1?, as depletion of CK1? reduced levels of phosphorylated FOXO3A and increased expression of FOXO3A-responsive genes. Oncogenic RAS increased CK1? protein abundance via activation of the PI3K/AKT/mTOR pathway. In turn, elevated levels of CK1? increased phosphorylation of nuclear FOXO3A, thereby inhibiting transactivation of genes critical for RAS-induced autophagy. In both RAS-driven cancer cells and murine xenograft models, pharmacologic CK1? inactivation synergized with lysosomotropic agents to inhibit growth and promote tumor cell death. Together, our results identify a kinase feedback loop that influences RAS-dependent autophagy and suggest that targeting CK1?-regulated autophagy offers a potential therapeutic opportunity to treat oncogenic RAS-driven cancers.

| S-EPMC4396475 | biostudies-literature

Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers.

Project description:Pancreatic ductal adenocarcinoma (PDA) was responsible for ~ 44,000 deaths in the United States in 2018 and is the epitome of a recalcitrant cancer driven by a pharmacologically intractable oncoprotein, KRAS1-4. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis5. However, paradoxically, inhibition of this pathway has provided no clinical benefit to patients with PDA6. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling elicits autophagy, a process of cellular recycling that protects PDA cells from the cytotoxic effects of KRAS pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of the LKB1→AMPK→ULK1 signaling axis, a key regulator of autophagy. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro and promotes regression of xenografted patient-derived PDA tumors in mice. The observed effect of combination trametinib plus chloroquine was not restricted to PDA as other tumors, including patient-derived xenografts (PDX) of NRAS-mutated melanoma and BRAF-mutated colorectal cancer displayed similar responses. Finally, treatment of a patient with PDA with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers.

| S-EPMC6452642 | biostudies-other

Regulation of PD-L1 expression in K-ras-driven cancers through ROS-mediated FGFR1 signaling.

Project description:K-ras mutations are major genetic events that drive cancer development associated with aggressive malignant phenotypes, while expression of the immune checkpoint molecule PD-L1 plays a key role in cancer evasion of the immune surveillance that also profoundly affects the patient outcome. However, the relationship between K-ras oncogenic signal and PD-L1 expressions as an important area that requires further investigation. Using both in vitro and in vivo experimental models of K-ras-driven cancer, we found that oncogenic K-ras significantly enhanced PD-L1 expression through a redox-mediated mechanism. Activation of K-rasG12V promoted ROS generation and induced FGFR1 expression, leading to a significant upregulation of PD-L1. We further showed that exogenous ROS such as hydrogen peroxide alone was sufficient to activate FGFR1 and induce PD-L1, while antioxidants could largely abrogate PD-L1 expression in K-ras mutant cells, indicating a critical role of redox regulation. Importantly, genetic knockout of FGFR1 led to a decrease in PD-L1 expression, and impaired tumor growth in vivo due to a significant increase of T cell infiltration in the tumor tissues and thus enhanced T-cell-mediated tumor suppression. Our study has identified a novel mechanism by which K-ras promotes PD-L1 expression, and suggests that modulation of ROS or inhibition of the FGFR1 pathway could be a novel strategy to abrogate PD-L1-mediated immunosuppression and thus potentially improve the efficacy of immunotherapy in K-ras-driven cancers.

| S-EPMC7658718 | biostudies-literature

Autophagy Inhibition in BRAF-Driven Cancers.

Project description:Several BRAF-driven cancers, including advanced BRAFV600E/K-driven melanoma, non-small-cell lung carcinoma, and thyroid cancer, are currently treated using first-line inhibitor combinations of BRAFV600E plus MEK1/2. However, despite the success of this vertical inhibition strategy, the durability of patient response is often limited by the phenomenon of primary or acquired drug resistance. It has recently been shown that autophagy, a conserved cellular recycling process, is increased in BRAF-driven melanoma upon inhibition of BRAFV600E signaling. Autophagy is believed to promote tumor progression of established tumors and also to protect cancer cells from the cytotoxic effects of chemotherapy. To this end, BRAF inhibitor (BRAFi)-resistant cells often display increased autophagy compared to responsive lines. Several mechanisms have been proposed for BRAFi-induced autophagy, such as activation of the endoplasmic reticulum (ER) stress gatekeeper GRP78, AMP-activated protein kinase, and transcriptional regulation of the autophagy regulating transcription factors TFEB and TFE3 via ERK1/2 or mTOR inhibition. This review describes the relationship between BRAF-targeted therapy and autophagy regulation, and discusses possible future treatment strategies of combined inhibition of oncogenic signaling plus autophagy for BRAF-driven cancers.

| S-EPMC8306561 | biostudies-literature

Transcriptional regulation of autophagy-lysosomal function in BRAF-driven melanoma progression and chemoresistance.

Project description:Autophagy maintains homeostasis and is induced upon stress. Yet, its mechanistic interaction with oncogenic signaling remains elusive. Here, we show that in BRAFV600E-melanoma, autophagy is induced by BRAF inhibitor (BRAFi), as part of a transcriptional program coordinating lysosome biogenesis/function, mediated by the TFEB transcription factor. TFEB is phosphorylated and thus inactivated by BRAFV600E via its downstream ERK independently of mTORC1. BRAFi disrupts TFEB phosphorylation, allowing its nuclear translocation, which is synergized by increased phosphorylation/inactivation of the ZKSCAN3 transcriptional repressor by JNK2/p38-MAPK. Blockade of BRAFi-induced transcriptional activation of autophagy-lysosomal function in melanoma xenografts causes enhanced tumor progression, EMT-transdifferentiation, metastatic dissemination, and chemoresistance, which is associated with elevated TGF-β levels and enhanced TGF-β signaling. Inhibition of TGF-β signaling restores tumor differentiation and drug responsiveness in melanoma cells. Thus, the "BRAF-TFEB-autophagy-lysosome" axis represents an intrinsic regulatory pathway in BRAF-mutant melanoma, coupling BRAF signaling with TGF-β signaling to drive tumor progression and chemoresistance.

| S-EPMC6461621 | biostudies-literature

The Metabolic Landscape of RAS-Driven Cancers from biology to therapy.

Project description:Our understanding of how the RAS protein family, and in particular mutant KRAS promote metabolic dysregulation in cancer cells has advanced significantly over the last decade. In this Review, we discuss the metabolic reprogramming mediated by oncogenic RAS in cancer, and elucidating the underlying mechanisms could translate to novel therapeutic opportunities to target metabolic vulnerabilities in RAS-driven cancers.

| S-EPMC8045781 | biostudies-literature

RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers.

Project description:Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.

| S-EPMC6115280 | biostudies-literature

Autophagy-dependent production of secreted factors facilitates oncogenic RAS-driven invasion.

Project description:The tumor-promoting functions of autophagy are primarily attributed to its ability to promote cancer cell survival. However, emerging evidence suggests that autophagy plays other roles during tumorigenesis. Here, we uncover that autophagy promotes oncogenic RAS-driven invasion. In epithelial cells transformed with oncogenic RAS, depletion of autophagy-related genes suppresses invasion in three-dimensional culture, decreases cell motility, and reduces pulmonary metastases in vivo. Treatment with conditioned media from autophagy-competent cells rescues the invasive capacity of autophagy-deficient cells, indicating that these cells fail to secrete factors required for RAS-driven invasion. Reduced autophagy diminishes the secretion of the promigratory cytokine interleukin-6 (IL-6), which is necessary to restore invasion of autophagy-deficient cells. Moreover, autophagy-deficient cells exhibit reduced levels of matrix metalloproteinase 2 and WNT5A. These results support a previously unrecognized function for autophagy in promoting cancer cell invasion via the coordinate production of multiple secreted factors.Our results delineate a previously unrecognized function for autophagy in facilitating oncogenic RAS-driven invasion. We demonstrate that an intact autophagy pathway is required for the elaboration of multiple secreted factors favoring invasion, including IL-6.

| S-EPMC3980002 | biostudies-literature

Inference of transcriptional regulation in cancers.

Project description:Despite the rapid accumulation of tumor-profiling data and transcription factor (TF) ChIP-seq profiles, efforts integrating TF binding with the tumor-profiling data to understand how TFs regulate tumor gene expression are still limited. To systematically search for cancer-associated TFs, we comprehensively integrated 686 ENCODE ChIP-seq profiles representing 150 TFs with 7484 TCGA tumor data in 18 cancer types. For efficient and accurate inference on gene regulatory rules across a large number and variety of datasets, we developed an algorithm, RABIT (regression analysis with background integration). In each tumor sample, RABIT tests whether the TF target genes from ChIP-seq show strong differential regulation after controlling for background effect from copy number alteration and DNA methylation. When multiple ChIP-seq profiles are available for a TF, RABIT prioritizes the most relevant ChIP-seq profile in each tumor. In each cancer type, RABIT further tests whether the TF expression and somatic mutation variations are correlated with differential expression patterns of its target genes across tumors. Our predicted TF impact on tumor gene expression is highly consistent with the knowledge from cancer-related gene databases and reveals many previously unidentified aspects of transcriptional regulation in tumor progression. We also applied RABIT on RNA-binding protein motifs and found that some alternative splicing factors could affect tumor-specific gene expression by binding to target gene 3'UTR regions. Thus, RABIT (rabit.dfci.harvard.edu) is a general platform for predicting the oncogenic role of gene expression regulators.

| S-EPMC4485084 | biostudies-other

The value of genomics in dissecting the RAS-network and in guiding therapeutics for RAS-driven cancers.

Project description:The rise in genomic knowledge over the past decade has revealed the molecular etiology of many diseases, and has identified intricate signaling network activity in human cancers. Genomics provides the opportunity to determine genome structure and capture the activity of thousands of molecular events concurrently, which is important for deciphering highly complex genetic diseases such as cancer. In this review, we focus on genomic efforts directed towards one of cancer's most frequently mutated networks, the RAS pathway. Genomic tools such as gene expression signatures and assessment of mutations across the RAS network enable the capture of RAS signaling complexity. Due to this high level of interaction and cross-talk within the network, efforts to target RAS signaling in the clinic have generally failed, and we currently lack the ability to directly inhibit the RAS protein with high efficacy. We propose that the use of gene expression data can identify effective treatments that broadly inhibit the RAS network as this approach measures pathway activity independent of mutation status or any single mechanism of activation. Here, we review the genomic studies that map the complexity of the RAS network in cancer, and that show how genomic measurements of RAS pathway activation can identify effective RAS inhibition strategies. We also address the challenges and future directions for treating RAS-driven tumors. In summary, genomic assessment of RAS signaling provides a level of complexity necessary to accurately map the network that matches the intricacy of RAS pathway interactions in cancer.

| S-EPMC5951171 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data