Three-Dimensional Collagen I Promotes Gemcitabine Resistance in Pancreatic Cancer through MT1-MMP–Mediated Expression of HMGA2

Abstract

One of the hallmarks of human pancreatic ductal adenocarcinoma (PDAC) is its pronounced type I collagenrich fibrotic reaction. Although recent reports have shown that the fibrotic reaction can limit the efficacy of gemcitabine chemotherapy, the underlying mechanisms remain poorly understood. In this article, we show that the type I collagen allows PDAC cells to override checkpoint arrest induced by gemcitabine. Relative to cells grown on tissue culture plastic, PDAC cells grown in 3-dimensional collagen microenvironment have minimal Chk1 phosphorylation and continue to proliferate in the presence of gemcitabine. Collagen increases membrane type 1 matrix metalloproteinase (MT1-MMP)-dependent ERK1/2 phosphorylation to limit the effect of gemcitabine. Collagen also increases MT1-MMP-dependent high mobility group A2 (HMGA2) expression, a nonhistone DNA-binding nuclear protein involved in chromatin remodeling and gene transcription, to attenuate the effect of gemcitabine. Overexpression of MT1-MMP in the collagen microenvironment increases ERK1/2 phosphorylation and HMGA2 expression, and thereby further attenuates gemcitabine-induced checkpoint arrest. MT1-MMP also allows PDAC cells to continue to proliferate in the presence of gemcitabine in a xenograft mouse model. Clinically, human tumors with increased MT1-MMP show increased HMGA2 expression. Overall, our data show that collagen upregulation of MT1-MMP contributes to gemcitabine resistance in vitro and in a xenograft mouse model, and suggest that targeting MT1-MMP could be a novel approach to sensitize pancreatic tumors to gemcitabine. Cancer Res; 71(3); 1019-28. Ó2010 AACR.

Cancer Cell Invasion in Three-dimensional Collagen Is Regulated Differentially by Gα13 Protein and Discoidin Domain Receptor 1-Par3 Protein Signaling

“…After 72 h, cells were extracted from the gels using collagenase and lysed in radioimmune precipitation assay buffer containing protease and phosphatase inhibitors for Western blotting (27,28).…”

HMGA2–FOXL2 Axis Regulates Metastases and Epithelial-to-Mesenchymal Transition of Chemoresistant Gastric Cancer

“…Previously, Fedele and colleagues reported that the interaction between HMGA2 and pRb enhanced the activity of E2F1 in pituitary tumorigenesis (25). pRb was a well-known repressor for E2F1 function.…”

“…4F). We then constructed a truncated Flag-tagged HMGA2 which could not interact with pRb (25), and established SGC7901 subline with stable expression of truncated HMGA2 (Fig. 4G).…”

“…HMGA2 functions as a regulator of cell proliferation and differentiation, and its expression has been found to be increased in a variety of human tumor tissues (22)(23)(24). Indeed, it has been reported that increased HMGA2 expression promotes metastasis and drug resistance in cancers of the gastrointestinal system (22)(23)(24)(25). HMGA2 was also suggested to be involved in EMT regulation based on the fact that increased HMGA2 expression was generally associated with EMT in many epithelial carcinomas (24,26,27).…”

Role of c-Src inhibitor in the regulation of hepatocarcinoma cell migration

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