Bone Morphogenetic Protein-2–Induced Transformation Involves the Activation of Mammalian Target of Rapamycin

Langenfeld, Elaine; Kong, Yingxin; Langenfeld, John

doi:10.1158/1541-7786.mcr-05-0124

Cited by 47 publications

(38 citation statements)

References 43 publications

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“…Stimulation of vascular smooth muscle cells with BMP2 induces cell motility in a phospho-AKT dependent manner via the action of Rac1 and RhoA GTPases [45]. In addition, activated BMP signalling enhances cell motility, invasion and EMT via the PI3 K-AKT pathway in other cancer cell types [46][47][48][49][50]. Thus, it will be important to identify whether BMP activation of AKT employs common or different mechanisms in EOC cells and spheroids, as well as the functional implications of this signalling on the malignant characteristics of EOC.…”

Section: Discussionmentioning

confidence: 99%

BMP signalling controls the malignant potential of ascites-derived human epithelial ovarian cancer spheroids via AKT kinase activation

Peart

Correa

Valdes³

et al. 2012

Clin Exp Metastasis

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Epithelial ovarian cancer (EOC) cells have the ability to form multi-cellular aggregates in malignant ascites which dramatically alters cell signalling, survival, and metastatic potential. Herein, we demonstrate that patient ascites-derived EOC cells down-regulate endogenous bone morphogenetic protein (BMP) signalling by decreasing BMP ligand expression when grown in suspension culture to form spheroids. Enforced BMP signalling in these cells via constitutively-active BMP type I ALK3(QD) receptor expression causes the formation of smaller, more loosely-aggregated spheroids. Additionally, ALK3(QD)-expressing spheroids have an increased rate of adhesion and dispersion upon reattachment to substratum. Inhibition of endogenous BMP signalling using recombinant Noggin or small molecule inhibitor LDN-193189, on the other hand, opposed these phenotypic changes. To identify potential targets that impact the phenotype of EOC spheroids due to activated BMP signalling, we performed genome-wide expression analyses using Affymetrix arrays. Using the online Connectivity Map resource, the BMP signalling gene expression signature revealed that the AKT pathway is induced by activated BMP signalling in EOC cells; this finding was further validated by phospho-AKT immuno-blotting. In fact, treatment of EOC spheroids with an AKT inhibitor, Akti-1/2, reduced BMP-stimulated cell dispersion during reattachment as compared to controls. Thus, we have identified AKT as being one important downstream component of activated BMP signalling on EOC spheroid pathobiology, which may have important implications on the metastatic potential of this malignancy.

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Section: Discussionmentioning

confidence: 99%

BMP signalling controls the malignant potential of ascites-derived human epithelial ovarian cancer spheroids via AKT kinase activation

Peart

Correa

Valdes³

et al. 2012

Clin Exp Metastasis

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“…BMP-2 was found to be overexpressed in primary human lung cancer compared with normal tissue (18) and was shown to activate Smad1/5, to increase Id1 expression, and to promote invasion in lung cancer cells (40,41). Critical regulatory elements in the Id1 promoter include a BMP-responsive region, a serum-responsive region, and a region associated with constitutive expression in breast cancer cells (14)(15)(16)34).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Id1 Expression by Src: Implications for Targeting of the Bone Morphogenetic Protein Pathway in Cancer

et al. 2008

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Deregulated activation of the Src tyrosine kinase and heightened Id1 expression are independent mediators of aggressive tumor biology. The present report implicates Src signaling as a critical regulator of Id1 gene expression. Microarray analyses showed that Id family genes were among the most highly down-regulated by incubation of A549 lung carcinoma cells with the small-molecule Src inhibitor AZD0530. Id1 transcript and protein levels were potently reduced in a dose-dependent manner concomitantly with the reduction of activated Src levels. These effects were conserved across a panel of lung, breast, prostate, and colon cancer cell lines and confirmed by the ability of PP2, Src siRNA, and Srcblocking peptides to suppress Id1 expression. PP2, AZD0530, and dominant-negative Src abrogated Id1 promoter activity, which was induced by constitutively active Src. The Srcresponsive region of the Id1 promoter was mapped to a region 1,199 to 1,360 bps upstream of the translation start site and contained a Smad-binding element. Src was also required for bone morphogenetic protein-2 (BMP-2)-induced Id1 expression and promoter activity, was moderately activated by BMP-2, and complexed with Smad1/5. Conversely, Src inhibitors blocked Smad1/5 nuclear translocation and binding to the Src-responsive region of the Id1 promoter. Consistent with a role for Src and Id1 in cancer cell invasion, Src inhibitors and Id1 siRNA decreased cancer cell invasion, which was increased by Id1 overexpression. Taken together, these results reveal that Src positively interacts with the BMP-Smad-Id pathway and provide new ways for targeted inhibition of Id1. [Cancer Res 2008;68(7):2250-8]

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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%

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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Bone Morphogenetic Protein-2–Induced Transformation Involves the Activation of Mammalian Target of Rapamycin

Cited by 47 publications

References 43 publications

BMP signalling controls the malignant potential of ascites-derived human epithelial ovarian cancer spheroids via AKT kinase activation

BMP signalling controls the malignant potential of ascites-derived human epithelial ovarian cancer spheroids via AKT kinase activation

Regulation of Id1 Expression by Src: Implications for Targeting of the Bone Morphogenetic Protein Pathway in Cancer

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

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