title: Bufalin Induces Mitochondria-Dependent Apoptosis in Pancreatic and Oral Cancer Cells by Downregulating hTERT Expression via Activation of the JNK/p38 Pathway.
abstract: Bufalin, a digoxin-like active component of the traditional Chinese medicine Chan Su, exhibits potent antitumor activities in many human cancers. Bufalin induces mitochondria-dependent apoptosis in cancer cells, but the detailed molecular mechanisms are largely unknown. hTERT, the catalytic subunit of telomerase, protects against mitochondrial damage by binding to mitochondrial DNA and reducing mitochondrial ROS production. In the present study, we investigated the effects of bufalin on the cell viability, ROS production, DNA damage, and apoptosis of CAPAN-2 human pancreatic and CAL-27 human oral cancer cells. Bufalin reduced CAPAN-2 and CAL-27 cell viability with IC50 values of 159.2 nM and 122.6 nM, respectively. The reduced cell viability was accompanied by increased ROS production, DNA damage, and apoptosis and decreased expression of hTERT. hTERT silencing in CAPAN-2 and CAL-27 cells by siRNA resulted in increased caspase-9/-3 cleavage and DNA damage and decreased cell viability. Collectively, these data suggest that bufalin downregulates hTERT to induce mitochondria-dependent apoptosis in CAPAN-2 and CAL-27 cells. Moreover, bufalin increased the phosphorylation of JNK and p38-MAPK in CAPAN-2 and CAL-27 cells, and blocking the JNK/p38-MAPK pathway using the JNK inhibitor SP600125 or the p38-MAPK inhibitor SB203580 reversed bufalin-induced hTERT downregulation. Thus, the JNK/p38 pathway is involved in bufalin-induced hTERT downregulation and subsequent induction of apoptosis by the mitochondrial pathway.
authors.affiliation: Molecular Oncology Laboratory of Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang 110001, China; Institute of Pathology and Pathophysiology, Shenyang 110001, China.
authors.forename: Shundong
authors.initials: S
authors.lastname: Dai
authors.affiliation: Department of Immunology and Biotherapy, Liaoning Cancer Hospital and Institute, Shenyang 110042, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Shenyi
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Molecular Oncology Laboratory of Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Chengguang
authors.initials: C
authors.lastname: Sui
authors.affiliation: Molecular Oncology Laboratory of Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Fandong
authors.initials: F
authors.lastname: Meng
authors.affiliation: Molecular Oncology Laboratory of Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Molecular Oncology Laboratory of Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Liye
authors.initials: L
authors.lastname: Fu
authors.affiliation: Molecular Oncology Laboratory of Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Molecular Oncology Laboratory of Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Molecular Oncology Laboratory of Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Su
authors.affiliation: Molecular Oncology Laboratory of Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Youhong
authors.initials: Y
authors.lastname: Jiang