AICAR activates ER stress-dependent apoptosis in gallbladder cancer cells

Abstract

AICAR (5-Aminoimidazole-4-carboxamide riboside or acadesine) is an AMP-activated protein kinase (AMPK) agonist, its activity in human gallbladder cancer cells was evaluated here. We show that AICAR provoked significant apoptosis in human gallbladder cancer cell lines (Mz-ChA-1, QBC939 and GBC-SD) and primary gallbladder cancer cells. AICAR-induced cytotoxicity in gallbladder cancer cells appears independent of AMPK activation. Inhibition of AMPK, via AMPKα shRNA knockdown or dominant negative mutation (T172A), failed to rescue GBC-SD cells from AICAR. Further, forced-activation of AMPK, by adding two other AMPK activators (A769662 and Compound 13), or expressing a constitutively-active mutant AMPKα (T172D), didn't induce GBC-SD cell death. Remarkably, AICAR treatment in gallbladder cancer cells induced endoplasmic reticulum (ER) stress activation, the latter was tested by caspase-12 activation, C/EBP homologous protein (CHOP) expression and IRE1/PERK phosphorylation. Contrarily, salubrinal (the ER stress inhibitor), z-ATAD-fmk (the caspase-12 inhibitor) or CHOP shRNAs significantly attenuated AICAR-induced gallbladder cancer cell apoptosis. Together, we conclude that AICAR-induced gallbladder cancer cell apoptosis requires ER stress activation, but is independent of AMPK.

AICA‐ribosiduria due to ATIC deficiency: Delineation of the phenotype with three novel cases, and long‐term update on the first case

“…For instance, it is able to induce programmed necrosis in prostate cancer cells through a cytotoxic mechanism involving reactive oxygen species 18 . AICAR/ZMP is also capable of inducing cellular apoptosis in human osteosarcoma cells, 19 or in gallbladder cancer cells through a cytotoxic mechanism involving endoplasmic reticulum‐stress activation 20 . AICA‐riboside has also demonstrated pro‐apoptotic abilities in a cellular model of von Hippel‐Lindau renal carcinoma and been able to reduce the size of renal tumors in a mouse model 21 .…”

“…18 AICAR/ ZMP is also capable of inducing cellular apoptosis in human osteosarcoma cells, 19 or in gallbladder cancer cells through a cytotoxic mechanism involving endoplasmic reticulum-stress activation. 20 AICA-riboside has also demonstrated pro-apoptotic abilities in a cellular model of von Hippel-Lindau renal carcinoma and been able to reduce the size of renal tumors in a mouse model. 21 Its AMPK-independent anti-tumoral properties could result from the activation of the tumor suppressor genes LATS1 and LATS2.…”

Anti-tumor Activity of Bufalin by Inhibiting c-MET Mediated MEK/ERK and PI3K/AKT Signaling Pathways in Gallbladder Cancer

“…Normal human gallbladder epithelial cells were not necessarily used as control cells in most articles [10][11][12][13][14]. The primary cells of human gallbladder epithelium were isolated and used as the research objects in a few articles according to their research needs [15]. Since the purpose of this study is to evaluate the effect of Bufalin on gallbladder cancer cells, the results of this study mainly reflect the changes of biological characteristics of human gallbladder cancer epithelial cells before and after treatment.…”

2‑Cl‑IB‑MECA regulates the proliferative and drug resistance pathways, and facilitates chemosensitivity in pancreatic and liver cancer cell lines

“…In addition, a study by Yung et al ( 77 ) demonstrated increased Ser 473 phosphorylation alongside decreased Thr 308 AKT residues that were modulated by ER stress in choriocarcinoma cells. In addition, previous descriptions of the ER stress response in tumor cells related to treatments with adenosine ( 78 ) and its analogue AICAR ( 79 ) further supports the notion.…”