Lamin B1 Is a Novel Therapeutic Target of Betulinic Acid in Pancreatic Cancer

Abstract

PURPOSE: Betulinic acid, a naturally occurring pentacyclic triterpenoid, exhibits potent antitumor activities, whereas the underlying mechanisms remain unclear. In the current study, we sought to determine the role and regulation of lamin B1 expression in human pancreatic cancer pathogenesis and betulinic acid-based therapy. EXPERIMENTAL DESIGN: We used cDNA microarray to identify betulinic acid target genes and used tissue microarray to determine the expression levels of lamin B1 in pancreatic cancer tissues and to define their relationship with the clinicopathologic characteristics of pancreatic cancer. We also used in vitro and in vivo models to determine the biologic impacts of altered lamin B1 expression on and mechanisms underlying lamin B1 overexpression in human pancreatic cancer. RESULTS: We found that lamin B1 was significantly downregulated by betulinic acid treatment in pancreatic cancer in both in vitro culture and xenograft models. Overexpression of lamin B1 was pronounced in human pancreatic cancer, and increased lamin B1 expression was directly associated with low-grade differentiation, increased incidence of distant metastasis, and poor prognosis of patients with pancreatic cancer. Furthermore, knockdown of lamin B1 significantly attenuated the proliferation, invasion, and tumorigenicity of pancreatic cancer cells. CONCLUSIONS: Lamin B1 plays an important role in pancreatic cancer pathogenesis and is a novel therapeutic target of betulinic acid treatment.