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

Abstract

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.

Increased Expression of Gremlin1 Promotes Proliferation and Epithelial Mesenchymal Transition in Gastric Cancer Cells and Correlates With Poor Prognosis of Patients With Gastric Cancer

“…For instance, BMP signalling could directly activate the expression of the EMT transcription factors, Snail, TWIST1 and MSX1/2 (36)(37)(38). Regarding the Smad-independent pathway, BMP2 could induce EMT and invasion through regulation of the PI3K/Akt pathway (39,40). In the current study, we found that the expression levels of GREM1were negatively correlated with the expression of ID1, ID2 and ID3, but were positively correlated with Snai1, SNAI2 and TWIST1.…”

“…Regulation of EMT by BMPs has been implicated in many studies regarding organ development (30,31) and cancer (32)(33)(34)(35). BMPs can induce EMT by both Smad-dependent (36)(37)(38) and Smad-independent pathways (39,40). For instance, BMP signalling could directly activate the expression of the EMT transcription factors, Snail, TWIST1 and MSX1/2 (36)(37)(38).…”

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

“…Activation of the BMP pathway induces the accumulation of SMAD proteins in the nucleus, which can subsequently activate EMT-related transcription factors such as SNAI1/2 and zinc finger E-box-binding homeobox 1/2 (ZEB1/2) (43). Moreover, activation of ACVR1 can lead to phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling (43)(44)(45). This can induce mesenchymal transition and contribute to invasion, as all three of these pathways are known to activate EMT-related transcription factors, including twist-related protein 1 (TWIST1) ( Figure 1C).…”

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

“…The role of TGFβ in EMT was first shown 25 years ago (30) and is still widely reported; a keyword search for "TGFβ EMT" returns 19,585 results in PMC (27th Sept 2019). Other stimuli known to induce EMT (Figure 1) include epidermal growth factor (EGF) (31,32), fibroblast growth factor (FGF) (33), hepatocyte growth factor (HGF) (34,35), vascular endothelial growth factor (VEGF) (36)(37)(38), insulin-like growth factor (IGF) (39,40), WNT (41), Sonic Hedgehog (SHH) (42,43), BMPs [BMP-2 (44,45); BMP-4 (46, 47)], TNF-α (48,49), and hypoxia (32) with the latter thought to promote EMT via epigenetic regulation of DICER; the enzyme involved in miRNA processing (50).…”