Targeting CREB for Cancer Therapy: Friend or Foe

Xiao, Xiangshu; Li, Bingbing X; Mitton, Bryan; Ikeda, Alan K.; Sakamoto, Kathleen M.

doi:10.2174/156800910791208535

Cited by 139 publications

(175 citation statements)

References 75 publications

Supporting

Mentioning

164

Contrasting

Order By: Relevance

“…In addition to the K-RAS V12 transformants described in this study an upregulated CREB expression and activation was detected in human tumors of distinct origin and appear to contribute to the initiation, progression, and metastatic potential of tumors as well as to a reduced patients' survival (38). In some of these tumor entities, mutations in the ras gene frequently occur, such as colon and lung carcinoma (25,26,39), but a direct link between RAS overexpression and/or mutation and CREB activity has not yet been determined.…”

Section: Discussionmentioning

confidence: 56%

“…This might be mediated by an increased expression of MHC class I surface antigens in shCREB K-RAS V12 transformants (personal communication). Thus, modulation of CREB expression and/or activity might be a potential therapeutic strategy of tumors for growth inhibition (38). This hypothesis is supported by (i) the use of the KIX/KID inhibitor KG-501 leading to a reduced proliferation and migration capacity as well as (ii) by using a dominant negative A-CREB protein inhibiting the DNA binding of the CREB TF family.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Colorectal Carcinogenesis: Connecting K-RAS–Induced Transformation and CREB Activity In Vitro and In Vivo

Steven

Heiduk

Recktenwald

et al. 2015

Molecular Cancer Research

View full text Add to dashboard Cite

Oncogenic transformation is often associated with an increased expression of the cAMP response element binding (CREB) transcription factor controlling the expression of genes involved in cell proliferation, cell cycle, apoptosis, and tumor development, but a link between K-RAS V12 -induced transformation and CREB has not yet been determined. Therefore, the constitutive and/or inhibitor-regulated mRNA and protein expression of CREB and signal transduction components and growth properties of parental fibroblasts, K-RAS V12 -transformed counterparts, shCREB K-RAS V12 transfectants and human colon carcinoma cells were determined. Increased CREB transcript and protein levels accompanied by an enhanced CREB activity was detected in K-RAS V12 -transformed murine fibroblasts and K-RAS V12 -mutated human tumor cells, which is dependent on the MAPK/MEK, PI3K, and/or PKC signal transduction. Immunohistochemical (IHC) staining of colorectal carcinoma lesions and murine tumors, with known KRAS gene mutation status, using antibodies specific for CREB and phospho-CREB, revealed a mechanistic link between CREB expression and K-RAS V12 -mutated colorectal carcinoma lesions when compared with control tissues. Silencing of CREB by shRNA and/or treatment with a CREB inhibitor (KG-501) reverted the neoplastic phenotype of K-RAS V12 transformants as demonstrated by a more fibroblast-like morphology, enhanced apoptosis sensitivity, increased doubling time, decreased migration, invasion and anchorage-independent growth, reduced tumorigenesis, and enhanced immunogenicity in vivo. The impaired shCREB-mediated invasion of K-RAS V12 transformants was accompanied by a transcriptional downregulation of different matrix metalloproteinases (MMP) coupled with their reduced enzymatic activity.Implications: CREB plays a key role in the K-RAS V12

show abstract

Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 97%

Colorectal Carcinogenesis: Connecting K-RAS–Induced Transformation and CREB Activity In Vitro and In Vivo

Steven

Heiduk

Recktenwald

et al. 2015

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…The transcription factor CREB1 is crucial for the generation of a malignant autocrine TGFβ2 loop, and hence CREB1 expression/phosphorylation levels might be considered a biomarker of response to anti-TGFβ treatments. Moreover, because CREB1 has been described as a putative therapeutic target ( 36,37 ), our results suggest that compounds against CREB1 could be effective anticancer agents due to their effect on the oncogenic levels of TGFβ2.…”

Section: Research Articlementioning

confidence: 70%

Active CREB1 Promotes a Malignant TGFβ2 Autocrine Loop in Glioblastoma

Rodón¹,

Gonzàlez-Juncà²,

Inda³

et al. 2014

Cancer Discovery

View full text Add to dashboard Cite

In advanced cancer, including glioblastoma, the TGFβ pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGFβ activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGFβ can induce TGFβ2, generating an autocrine loop leading to aberrantly high levels of TGFβ2. We identifi ed cAMP-responsive element-binding protein 1 (CREB1) as the critical mediator of the induction of TGFβ2 by TGFβ. CREB1 binds to the TGFB2 gene promoter in cooperation with SMAD3 and is required for TGFβ to activate transcription. Moreover, the PI3K-AKT and RSK pathways regulate the TGFβ2 autocrine loop through CREB1. The levels of CREB1 and active phosphorylated CREB1 correlate with TGFβ2 in glioblastoma. In addition, using patient-derived in vivo models of glioblastoma, we found that CREB1 levels determine the expression of TGFβ2. Our results show that CREB1 can be considered a biomarker to stratify patients for anti-TGFβ treatments and a therapeutic target in glioblastoma. SIGNIFICANCE:TGFβ is considered a promising therapeutic target, and several clinical trials using TGFβ inhibitors are generating encouraging results. Here, we discerned the molecular mechanisms responsible for the aberrantly high levels of TGFβ2 found in certain tumors, and we propose biomarkers to predict the clinical response to anti-TGFβ therapies. Cancer Discov; 4(10); 1230-41.

show abstract

“…Tissue embedding, histology, and immunhistochemistry For the paraffin-embedded human tissues samples, antigen retrieval was performed by microwave treatment for 10 minutes at 750 W in 10 mmol/L of sodium citrate buffer, pH 6.0, and then the 5-mm sections were incubated overnight at 4 C with the pCREB-specific rabbit antibody (clone 87G3; Cell Signaling Technology) at a 1:50 dilution. Antirabbit EnVision kits (K4003, Dako) were used for signal amplification.…”

Section: Patient Selection and Tissue Microarraysmentioning

confidence: 99%

“…1, 2). CREB can be phosphorylated by many different protein kinases, including protein kinase A (PKA), protein kinase B (PKB)/Akt, mitogen-activated protein kinases (MAPK), and p90 ribosomal S6 kinase (p90 metastasis (4,11,12). However, a direct link between oncogenic transformation and CREB has not yet been determined.…”

Section: Introductionmentioning

confidence: 99%

HER-2/neu Mediates Oncogenic Transformation via Altered CREB Expression and Function

Steven

Leisz

Massa

et al. 2013

Molecular Cancer Research

View full text Add to dashboard Cite

The cyclic (c)AMP responsive element binding protein (CREB) plays a key role in many cellular processes, including differentiation, proliferation, and signal transduction. Furthermore, CREB overexpression was found in tumors of distinct origin and evidence suggests an association with tumorigenicity. To establish a mechanistic link between HER-2/neu-mediated transformation and CREB protein expression and function, in vitro models of HER-2/neu-overexpressing and HER-2/neu-negative/silenced counterparts as well as human mammary carcinoma lesions with defined HER-2/neu status were used. HER-2/neu overexpression resulted in the induction and activation of CREB protein in vitro and in vivo, whereas short hairpin RNA (shRNA)-mediated inhibition of HER-2/neu correlated with downregulated CREB activity. CREB activation in HER-2/neu-transformed cells enhanced distinct signal transduction pathways, whereas their inhibition negatively interfered with CREB expression and/or activation. CREB downregulation in HER-2/neu-transformed cells by shRNA and by the inhibitors KG-501 and lapatinib caused morphologic changes, reduced cell proliferation with G 0 -G 1 cell-cycle arrest, which was rescued by CREB expression. This was accompanied by reduced cell migration, wound healing, an increased fibronectin adherence, invasion, and matrix metalloproteinase expression. In vivo shCREB-HER-2/neu þ cells, but not control cells, exerted a significantly decreased tumorgenicity that was associated with decreased proliferative capacity, enhanced apoptosis, and increased frequency of T lymphocytes in peripheral blood mononuclear cells. Thus, CREB plays an important role in the HER-2/neu-mediated transformation by altering in vitro and in vivo growth characteristics.

show abstract

Targeting CREB for Cancer Therapy: Friend or Foe

Cited by 139 publications

References 75 publications

Colorectal Carcinogenesis: Connecting K-RAS–Induced Transformation and CREB Activity In Vitro and In Vivo

Colorectal Carcinogenesis: Connecting K-RAS–Induced Transformation and CREB Activity In Vitro and In Vivo

Active CREB1 Promotes a Malignant TGFβ2 Autocrine Loop in Glioblastoma

HER-2/neu Mediates Oncogenic Transformation via Altered CREB Expression and Function

Contact Info

Product

Resources

About