BMP suppresses PTEN expression via RAS/ERK signaling

Beck, Stayce E.; Carethers, John M.

doi:10.4161/cbt.6.8.4507

Cited by 44 publications

(37 citation statements)

References 21 publications

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“…These finding indicate that alternative signaling pathways associated with BMP2 growth regulation may allow SW480 and DLD-1 cell survival in the presence of high concentrations of BMP2. In some cellular cancer models, for example, EMT and metastasis required cooperation of BMPs with the activated oncogenes such as RAS or activated receptor tyrosine kinases (8,16,(27)(28)(29). SW480 and DLD-1 cells used in the present studies express mutated K-RAS oncogenes.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, multiple non-Smad pathways have been implicated in mediating BMPs signaling. Studies in colon cancer cell lines have shown that BMP down-regulates PTEN via RAS/ERK in a SMAD4-null environment that contributes to cell growth, and constitutes a SMAD4-independent, but BMPresponsive signaling pathway (8). BMPs has also been shown to induce proliferation and colony formation of fetal pancreatic cells through phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways (9).…”

Section: Introductionmentioning

confidence: 99%

“…Integration of the BMP2 pathway with other signaling cascades may modulate BMP2 responses. In the N1511 chondrocytic cell line, it has been reported that BMP2 rapidly induces the phosphorylation of Akt and NF-κB activation and prevents an apoptotic effect of these cells (8,16). In colon cancer cells, BMP-SMAD signaling and growth suppression is facilitated by p21(WAF1), but modulated by oncogenic K-RAS to reduce the growth suppression directed by this pathway (8).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of PI3 kinase/Akt pathway is required for BMP2-induced EMT and invasion

Kang

Kim²,

Kim³

et al. 2009

Oncol Rep

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Abstract. Although dysregulation of bone morphogenetic protein (BMP) signaling has been linked to various types of cancers, the relationship between abnormal activation of these signaling pathways and tumorigenesis is not clear. The purpose of the current study was to clarify how BMP2 is involved in colon cancer aggressiveness. The data showed that SW480 and DLD-1 cells displayed different responses to short-and long-term exposure to BMP2. During the first 24 h of exposure to BMP2, these cells were growth-inhibited, whereas surviving cells became resistant to growth inhibition, showing epithelial-to-mesenchymal transformation (EMT) and enhanced motility and invasiveness. Interestingly, in highly metastatic mesenchymal colon carcinoma cells (CT26), blockade of BMP2 signaling by BMP2 siRNA prevented EMT, motility and invasiveness; rather, blockade of BMP2 signaling caused a mesenchymal-to-epithelial transition (MET). The levels of phosphorylated Akt were very different between the two cell types; the BMP2-sensitive SW480 and DLD-1 cells had much higher levels of expression than the BMP2-resistant SW480 and DLD-1 and CT26 cells. CT26 cells, following exposure to BMP2 and activation of Akt, escaped the EMT-induced cellular motility and invasiveness. Moreover, LY294002 treatment of BMP2-sensitive SW480 cells blocked cell growth and enhanced motility and invasiveness. Together, these results suggest that suppression of the PI3 kinase/Akt pathway is correlated with the development of BMP2 resistance and invasion in BMP2-induced EMT in colon cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of PI3 kinase/Akt pathway is required for BMP2-induced EMT and invasion

Kang

Kim²,

Kim³

et al. 2009

Oncol Rep

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“…Here, we observed Erk activation in response to BMP4 and TGF-b1 in MPNSTs. Ras may promote or abrogate different aspects of TGFb/BMP signaling (10,11,43). Importantly, in mouse mammary epithelial cells, the Ras/Raf/MEK/Erk signaling is necessary for the TGF-b-mediated induction of EMT tumorigenesis enhancement (44).…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Reversion of Invasive Neurofibromin-Deficient Schwannoma by FTS: Ras Inhibition Reduces BMP4/Erk/Smad Signaling

Barkan

Kloog

Ehrlich

2011

Molecular Cancer Therapeutics

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“…BMPs are members of the transforming growth factor beta (TGFβ) family; thus, BMPs utilize a similar signaling cascade to that of TGFβ. BMPs have been identified to utilize the SMAD signaling pathway for their growth suppressive effects, and also to affect PTEN and p21 (WAF1) expression via RAS-ERK signaling in cancer (10)(11)(12). Additionally, previous studies have revealed that genetic variations in BMP genes are associated with a number of types of cancer (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in bone morphogenetic protein 3 and the risk of papillary thyroid cancer

Kim¹,

Hong

Eun

et al. 2012

Oncology Letters

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Abstract. Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta (TGFβ) superfamily with well-described functions in bone formation. Although disrupted BMP signaling in tumor development has been investigated, a genetic association for BMP3 in papillary thyroid cancer (PTC) has remained largely unexplored. In this study, we investigated whether BMP3 single nucleotide polymorphisms (SNPs) are associated with the development of PTC and its clinicopathological features. A total of 103 PTC patients and 324 control subjects were enrolled. One promoter SNP (rs13138132; -1919C/A) and one missense mutation (rs3733549; Arg192Gln) in BMP3 were genotyped by direct sequencing. SNPStats, SNPAnalyzer, Helixtree and Haploview version 4.2 were used to evaluate the genetic data. Multiple logistic regression models were used to calculate odds ratios (ORs), 95% confidence intervals (CIs) and P-values. The missense SNP (rs3733549) was weakly associated with the development of PTC in a codominant model (AA vs. GG; P=0.017) and a recessive model (AA vs. GG/GA; P=0.023). Additionally, in an analysis according to clinicopathological features, rs13138132 was significantly associated with extrathyroidal invasion in a codominant model (CA vs. CC; P=0.006) and a dominant model (CA/AA vs. CC; P=0.0023). We also identified that the frequency of the A allele in the promoter SNP (rs13138132) was increased in PTC patients with extrathyroidal invasion (P=0.004). Our data suggest that rs3733549 in BMP3 is associated with the development of PTC and that the A allele of rs13138932 in BMP3 is a risk factor for extrathyroidal invasion. IntroductionThyroid cancer is the most common type of endocrine malignancy, accounting for approximately 1% of all cases of cancer. It is the most rapidly increasing cancer among females and the second most rapidly increasing cancer among males. Histologically, thyroid cancer is classified as papillary thyroid cancer (PTC), follicular thyroid cancer, medullary thyroid cancer or undifferentiated or anaplastic thyroid cancer. Of these, PTC is the most common type, and it accounts for 85-90% of all thyroid malignancies (1,2). Although the etiology of PTC is unclear, environmental factors, including radiation, diet, smoking and hormones, have been identified to affect the pathogenesis of thyroid cancer (3,4). Genetic predisposition has also been implicated as a risk factor for thyroid cancer development (5,6).Bone morphogenic proteins (BMPs) have been demonstrated to play an important role during development (particularly during bone formation) and in the regulation of various cellular processes, including cell proliferation, apoptosis and differentiation (7). Evidence suggests that BMPs are important in tumorigenesis (8-10). BMPs are members of the transforming growth factor beta (TGFβ) family; thus, BMPs utilize a similar signaling cascade to that of TGFβ. BMPs have been identified to utilize the SMAD signaling pathway for their growth suppressive effects, and also to affect PTEN and p21 (W...

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BMP suppresses PTEN expression via RAS/ERK signaling

Cited by 44 publications

References 21 publications

Inhibition of PI3 kinase/Akt pathway is required for BMP2-induced EMT and invasion

Inhibition of PI3 kinase/Akt pathway is required for BMP2-induced EMT and invasion

Phenotypic Reversion of Invasive Neurofibromin-Deficient Schwannoma by FTS: Ras Inhibition Reduces BMP4/Erk/Smad Signaling

Polymorphisms in bone morphogenetic protein 3 and the risk of papillary thyroid cancer

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