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EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity.

ABSTRACT: EGFR and its constitutively activated variant EGFRvIII are linked to glioblastoma resistance to therapy, the mechanisms underlying this association, however, are still unclear. We report that in glioblastoma, EGFR/EGFRvIII paradoxically co-expresses with p53-upregulated modulator of apoptosis (PUMA), a proapoptotic member of the Bcl-2 family of proteins primarily located on the mitochondria. EGFR/EGFRvIII binds to PUMA constitutively and under apoptotic stress, and subsequently sequesters PUMA in the cytoplasm. The EGFR-PUMA interaction is independent of EGFR activation and is sustained under EGFR inhibition. A Bcl-2/Bcl-xL inhibitor that mimics PUMA activity sensitizes EGFR/EGFRvIII-expressing glioblastoma cells to Iressa. Collectively, we uncovered a novel kinase-independent function of EGFR/EGFRvIII that leads to tumor drug resistance.

SUBMITTER: Zhu H

PROVIDER: S-EPMC2875288 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity.

Zhu Hu H Cao Xinyu X Ali-Osman Francis F Keir Stephen S Lo Hui-Wen HW

Cancer letters 20100213 1

EGFR and its constitutively activated variant EGFRvIII are linked to glioblastoma resistance to therapy, the mechanisms underlying this association, however, are still unclear. We report that in glioblastoma, EGFR/EGFRvIII paradoxically co-expresses with p53-upregulated modulator of apoptosis (PUMA), a proapoptotic member of the Bcl-2 family of proteins primarily located on the mitochondria. EGFR/EGFRvIII binds to PUMA constitutively and under apoptotic stress, and subsequently sequesters PUMA i ...[more]

PMID: 20153921

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PUMA mediates EGFR tyrosine kinase inhibitor-induced apoptosis in head and neck cancer cells.

Project description:Overexpression of epidermal growth factor receptor (EGFR) is found in over 80% of head and neck squamous cell carcinomas (HNSCC) and associated with poor clinical outcomes. EFGR selective tyrosine kinase inhibitors (TKIs) or antibodies have recently emerged as promising treatments for solid tumors, including HNSCC, though the response rate to these agents is low. p53 upregulated modulator of apoptosis (PUMA), a BH3-only Bcl-2 family protein, is required for apoptosis induced by p53 and various chemotherapeutic agents. In this study, we show that PUMA induction is correlated with EGFR-TKI sensitivity, and is mediated through the p53 family protein p73beta and inhibition of the PI3K/AKT pathway. In some HNSCC cells, the gefitinib-induced degradation of oncogenic Delta Np63 seems to facilitate p73-mediated PUMA transcription. Inhibiting PUMA expression by small hairpin RNA (shRNA) impairs gefitinib-induced apoptosis. Furthermore, PUMA or BH3 mimetics sensitize HNSCC cells to gefitinib-induced apoptosis. Our results suggest that PUMA induction through p73 represents a new mechanism of EGFR inhibitor-induced apoptosis, and provide potential ways for enhancing and predicting the sensitivity to EGFR-targeted therapies in HNSCC.

| S-EPMC2872091 | biostudies-literature

PUMA-mediated apoptosis drives chemical hepatocarcinogenesis in mice.

Project description:Hepatocyte death and proliferation contribute to hepatocellular carcinoma development after carcinogen exposure or chronic liver inflammation. However, the role and the molecular targets of hepatocyte death in relation to compensatory proliferation have not been fully characterized. In this study, we investigated the role of p53 up-regulated modulator of apoptosis (PUMA), a BH3-only protein important for both p53-dependent and -independent apoptosis, in a diethylnitrosamine (DEN)-induced liver carcinogenesis model. PUMA deficiency significantly decreased the multiplicity and size of liver tumors. DEN treatment induced p53-independent PUMA expression, PUMA-dependent hepatocyte death, and compensatory proliferation. Furthermore, inhibition or deletion of c-jun N-terminal kinase 1 (JNK1) abrogated PUMA induction, hepatocyte death, and compensatory proliferation.These results provide direct evidence that JNK1/PUMA-dependent apoptosis promotes chemical hepatocarcinogenesis through compensatory proliferation, and suggest apoptotic inducers as potential therapeutic targets in liver injury and cancer.

| S-EPMC3184207 | biostudies-literature

EGFR wild type antagonizes EGFRvIII-mediated activation of Met in glioblastoma.

Project description:Epidermal growth factor receptor (EGFR)vIII is the most common EGFR mutant found in glioblastoma (GBM). EGFRvIII does not bind ligand, is highly oncogenic and is usually coexpressed with EGFR wild type (EGFRwt). EGFRvIII activates Met, and Met contributes to EGFRvIII-mediated oncogenicity and resistance to treatment. Here, we report that addition of EGF results in a rapid loss of EGFRvIII-driven Met phosphorylation in glioma cells. Met is associated with EGFRvIII in a physical complex. Addition of EGF results in a dissociation of the EGFRvIII-Met complex with a concomitant loss of Met phosphorylation. Consistent with the abrogation of Met activation, addition of EGF results in the inhibition of EGFRvIII-mediated resistance to chemotherapy. Thus, our study suggests that ligand in the milieu of EGFRvIII-expressing GBM cells is likely to influence the EGFRvIII-Met interaction and resistance to treatment, and highlights a novel antagonistic interaction between EGFRwt and EGFRvIII in glioma cells.

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RNA-seq Analysis of U87: Ctrl, U87:EGFR, U87:EGFRvIII, U87:EGFR+EGFRvIII and U87:EGFR+EGFRvIII KRAS KO

Project description:We found that U87 cells expressing EGFR and EGFRvIII upregulated a large group of cytokines. The upregulation of many of these cytokines was dependent on KRAS.

2018-11-01 | GSE117838 | GEO

PUMA-mediated epithelial cell apoptosis promotes Helicobacter pylori infection-mediated gastritis.

Project description:The molecular mechanism responsible for Helicobacter pylori infection-mediated gastritis and carcinogenesis is not yet clear. Increased evidence suggests that chronic gastritis and elevated gastric epithelial cell (GEC) apoptosis are crucial events during stomach carcinoma transformation. PUMA is a potent proapoptotic Bcl-2 protein and mediates acute tissue injury. In this study, we aimed to investigate the role of PUMA in GEC apoptosis and inflammation induced by H. pylori infection. As a result, we found that PUMA expression was elevated in gastritis tissues compared with uninvolved tissues, and it was correlated with the severity of apoptosis and gastritis. In mice, PUMA mRNA and protein were markedly induced in GECs upon induction of gastritis by H. pylori. PUMA-deficient mice were highly resistant to apoptosis and gastritis induced by H. pylori. Furthermore, the transcription factor NF-?B p65 binds to PUMA promoter to activate PUMA transcription after H. pylori infection. In addition, NF-?B inhibitor could rescue H. pylori-induced apoptosis and gastritis. Finally, H. pylori-induced activation of p-p65 and PUMA was mediated via Toll-like receptor 2 (TLR2) and blocked in TLR2 knockout mice. Taken together, these results verified the pro-inflammatory effect of PUMA in H. pylori-infected gastric tissue. Moreover, TLR2/NF-?B-mediated transcriptional regulation of PUMA contributes to the pathogenesis of H. pylori-infected gastritis.

| S-EPMC7033162 | biostudies-literature

Chaperone-mediated autophagy prevents apoptosis by degrading BBC3/PUMA.

Project description:Autophagy is a potentially inimical pathway and together with apoptosis, may be activated by similar stress stimuli that can lead to cell death. The molecular cues that dictate the cell fate choice between autophagy and apoptosis remain largely unknown. Here we report that the proapoptotic protein BBC3/PUMA (BCL2 binding component 3) is a bona fide substrate of chaperone-mediated autophagy (CMA). BBC3 associates with HSPA8/HSC70 (heat shock 70kDa protein 8), leading to its lysosome translocation and uptake. Inhibition of CMA results in stabilization of BBC3, which in turn sensitizes tumor cells to undergo apoptosis. We further demonstrate that upon TNF (tumor necrosis factor) treatment, IKBKB/IKKβ (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase β)-mediated BBC3 Ser10 phosphorylation is crucial for BBC3 stabilization via blocking its degradation by CMA. Mechanistically, Ser10 phosphorylation facilitates BBC3 translocation from the cytosol to mitochondria. BBC3 stabilization resulting from either Ser10 phosphorylation or CMA inhibition potentiates TNF-induced apoptotic cell death. Our findings thus reveal that the selective degradation of BBC3 underlies the prosurvival role of CMA and define a previously unappreciated proapoptotic role of IKBKB that acts through phosphorylation-mediated stabilization of BBC3, thereby promoting TNF-triggered apoptosis.

| S-EPMC4590652 | biostudies-literature

Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis.

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| S-EPMC4079733 | biostudies-literature

Implication of TAp73 in the p53-independent pathway of Puma induction and Puma-dependent apoptosis in primary cortical neurons.

Project description:Puma (p53 up-regulated modulator of apoptosis) is a BH3-only protein member of the Bcl-2 family that controls apoptosis by regulating the release of pro-apoptotic factors from mitochondria. Previously, we reported that sodium arsenite (NaAsO(2)) induces Puma-dependent apoptosis in cortical neurons in a p53-independent manner. The following evidence shows that p53-independent Puma activation by NaAsO(2) is mediated by the p53-related protein TAp73: (i) NaAsO(2) causes TAp73alpha accumulation and increases p53-independent expression of p73 target genes; (ii) two p53 response elements in the Puma promoter are required for NaAsO(2)-mediated activation of a Puma reporter construct; (iii) expression of the inhibitory DeltaNp73alpha and DeltaNp73beta isoforms decreases NaAsO(2)-mediated induction of Puma and other p53-family target genes in a p53-null background; (iv) DeltaNp73alpha and DeltaNp73beta expression protects the neurons from NaAsO(2)-dependent apoptosis. Interestingly, although ER stressors also induce p53-independent, Puma-dependent apoptosis, they do not increase TAp73 expression while NaAsO(2) does not induce notable endoplasmic reticulum (ER) stress. In contrast, DNA damaging agents, okadaic acid, and H(2)O(2) all induce apoptosis in a strictly Puma- and p53-dependent manner. Hence, the pivotal position of Puma as mediator of apoptosis in cortical neurons is because of the availability of at least three independent signalling pathways that ensure its activation.

| S-EPMC2956137 | biostudies-literature

Eleostearic acid induces RIP1-mediated atypical apoptosis in a kinase-independent manner via ERK phosphorylation, ROS generation and mitochondrial dysfunction.

Project description:RIP1 is a serine/threonine kinase, which is involved in apoptosis and necroptosis. In apoptosis, caspase-8 and FADD have an important role. On the other hand, RIP3 is a key molecule in necroptosis. Recently, we reported that eleostearic acid (ESA) elicits caspase-3- and PARP-1-independent cell death, although ESA-treated cells mediate typical apoptotic morphology such as chromatin condensation, plasma membrane blebbing and apoptotic body formation. The activation of caspases, Bax and PARP-1, the cleavage of AIF and the phosphorylation of histone H2AX, all of which are characteristics of typical apoptosis, do not occur in ESA-treated cells. However, the underlying mechanism remains unclear. To clarify the signaling pathways in ESA-mediated apoptosis, we investigated the functions of RIP1, MEK, ERK, as well as AIF. Using an extensive study based on molecular biology, we identified the alternative role of RIP1 in ESA-mediated apoptosis. ESA mediates RIP1-dependent apoptosis in a kinase independent manner. ESA activates serine/threonine phosphatases such as calcineurin, which induces RIP1 dephosphorylation, thereby ERK pathway is activated. Consequently, localization of AIF and ERK in the nucleus, ROS generation and ATP reduction in mitochondria are induced to disrupt mitochondrial cristae, which leads to cell death. Necrostatin (Nec)-1 blocked MEK/ERK phosphorylation and ESA-mediated apoptosis. Nec-1 inactive form (Nec1i) also impaired ESA-mediated apoptosis. Nec1 blocked the interaction of MEK with ERK upon ESA stimulation. Together, these findings provide a new finding that ERK and kinase-independent RIP1 proteins are implicated in atypical ESA-mediated apoptosis.

| S-EPMC3702295 | biostudies-literature

Slug promotes survival during metastasis through suppression of Puma-mediated apoptosis.

Project description:Tumor cells must overcome apoptosis to survive throughout metastatic dissemination and distal organ colonization. Here, we show in the Polyoma Middle T mammary tumor model that N-cadherin (Cdh2) expression causes Slug (Snai2) upregulation, which in turn promotes carcinoma cell survival. Slug was dramatically upregulated in metastases relative to primary tumors. Consistent with a role in metastasis, Slug knockdown in carcinoma cells suppressed lung colonization by decreasing cell survival at metastatic sites, but had no effect on tumor cell invasion or extravasation. In support of this idea, Slug inhibition by shRNA sensitized tumor cells to apoptosis by DNA damage, resulting in caspase-3 and PARP cleavage. The prosurvival effect of Slug was found to be caused by direct repression of the proapoptotic gene, Puma (Bbc3), by Slug. Consistent with a pivotal role for a Slug-Puma axis in metastasis, inhibition of Puma by RNA interference in Slug-knockdown cells rescued lung colonization, whereas Puma overexpression in control tumor cells suppressed lung metastasis. The survival function of the Slug-Puma axis was confirmed in human breast cancer cells, where Slug knockdown increased Puma expression and inhibited lung colonization. This study demonstrates a pivotal role for Slug in carcinoma cell survival, implying that disruption of the Slug-Puma axis may impinge on the survival of metastatic cells.

| S-EPMC4437462 | biostudies-literature

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