BMP2 Induces PANC-1 cell invasion by MMP-2 overexpression through ROS and ERK

Abstract

The emerging roles of bone morphogenetic proteins (BMPs) in the initiation and progression of multiple cancers have drawn great attention in cancer research. We hypothesized that BMP2 promotes cancer metastasis by modulating MMP-2 secretion and activity through intracellular ROS regulation and ERK activation in human pancreatic cancer. Our data show that stimulation of PANC-1 cells with BMP2 induced MMP-2 secretion and activation, associated with decreased E-cadherin expression, resulting in epithelial-to-mesenchymal transformation (EMT) and cell invasion. Blockade of ROS by the ROS scavenger, 2-MPG, abolished cell invasion, inhibited the EMT process and decreased MMP-2 expression, suggesting ROS accumulation caused an increase in MMP-2 expression in BMP2-stimulated PANC-1 cell invasion. Furthermore, treatment of PANC-1 cells with 2-MPG or ERK inhibitor PD98059 reduced the phosphorylation of ERK, resulting in attenuation of BMP2-induced cell invasion and MMP-2 activation. Taken together, these results suggest that BMP2 induces the cell invasion of PANC-1 cells by enhancing MMP-2 secretion and acting through ROS accumulation and ERK activation.

CD166/ALCAM Expression Is Characteristic of Tumorigenicity and Invasive and Migratory Activities of Pancreatic Cancer Cells

“…The level of N-cadherin mRNA, a mesenchymal marker, was higher in CD166+ cells than that in CD166- cells. Furthermore, the level of metalloproteinase 2 (MMP2) mRNA, which is related to cell invasiveness, was increased in CD166- cells compared with that in CD166+ cells [22]. Next, we analyzed the relationship between CD166 expression and CSC markers CD24, CD44, and CD133; however, we did not find any significant changes in their expression between CD166+ and CD166- cells derived from Panc-1 cells (Figure 5D) [23], [24].…”

Polyserase-1/TMPRSS9 induces pro-tumor effects in pancreatic cancer cells by activation of pro-uPA

“…Matriptase is also able to activate pro-UPA in the ovarian cancer cell line HRA (29) and the monocytic leukemia cell line THP-1 (22). On the other hand, induction of invasive and migratory capacities of PANC-1 cells has been linked to activation of ERK by phosphorylation (30). Collectively, our data suggest that TMPRSS9 exerts pro-tumor effects on PANC-1 cancer cells overcoming apoptotic signals induced in anchorage-dependent cells when detaching from the surrounding ECM.…”

An Update of Bone Morphogenetic Proteins as Biomarker and Therapy for Cancer

“…However, studies support a tumorigenic role of BMP-2 in lung cancer [28,40]. Recent evidences also strongly indicate the positive role of BMP-2 on invasiveness of many cancers, such as gastric, bladder, pancreatic, oral, prostate and breast cancer [13,14,23,[41][42][43][44][45][46]. Expression of BMP-2 in cancer tissues often correlates with lymph node metastasis and bone metastasis [11,13,28].…”

“…In addition, BMP-2 signaling may also activate non-canonical PI3K/AKT, MAPKinase, NFκB [13,23,24,58] and also increases matrix mettaloproteinases (MMP-2 and MMP-9) activity which could be responsible for the invasion of cancer cells [13,23]. Recent literature evidences that BMP-2 treatment inhibits epithelial marker E-cadherin and promotes mesenchymal protein vimentin resulting in EMT of several cancer types such as gastric cancer, pancreatic cancer and lung cancer [23,24,41]. However, BMP-6 and BMP-7 may inhibit EMT of cancer cells such as breast, cholangio carcinoma, and melanoma cancer [52,59,60].…”

“…In non-canonical pathways, BMPs may activate various types of signaling such as PI3K/ AKT, MAPKinase, p38 etc. [13,[19][20][21][22][23][24][25]. Moreover, several signaling (e.g., Wnt signaling) cross talk to BMP pathway to modulate its functional activity [26].…”