Content area
Full Text
Introduction
Pancreatic adenocarcinoma is one of the most lethal and poorly understood human malignancies. Because of the lack of effective systemic therapies the 5-year survival rate for patients with pancreatic adenocarcinoma has remained at 1–3% without a change over the past 25 years (1,2). To date, the only potential curative means is surgical resection, of which only 20% of patients are eligible. Alternative therapies, such as radiotherapy and chemotherapy remain largely ineffective. Therefore, the development and evaluation of novel targeted therapeutic agents that reduce the intrinsic drug resistance of this disease poses one of the greatest challenges in pancreatic cancer research and other intractable cancers.
AMP-activated protein kinase (AMPK), a serine/threonine kinase, is a highly conserved sensor of cellular energy status in eukaryotes and is widely known as a regulator of cell metabolism (3). AMPK is a heterotrimeric protein consisting of a catalytic α-subunit and regulatory β-/γ-subunits (4,5). It is phosphorylated at Thr172 in response to an increase in the ratio of AMP-to-ATP within its activation domain of α-subunit by upstream kinases LKB1 (6–8) and calmodulin-dependent protein kinase kinase β (CaMKKβ) (9–11). Several previous studies show that excessive AMPK activation by treatment of AMPK activator (such as Metformin, 5-aminoimidazole-4-carboxamide riboside (AICAR) or A769662) inhibits the growth and/or survival of various cancer cell lines (12–19). Moreover, BML-275 (compound C), a potent, selective, and reversible ATP-competitive inhibitor of AMPK induces cell death in various types of cancers including myeloma, glioma, prostate and breast carcinoma cells (20–23). In addition, inhibition of AMPK pathway by compound C sensitizes apoptosis by co-treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), doxorubicin or cisplatin in human renal, leukemia, gastric carcinoma, colon carcinoma, and cervix adenocarcinoma cell lines (24–26). Therefore, pharmacological inhibition of AMPK activity might be potentially useful in therapy of human solid tumors. However, the effect of AMPK inhibition of pancreatic cancer cell proliferation or survival has not been investigated.
Cell cycle deregulation resulting in uncontrolled cell proliferation is the one of the most frequent alterations that occurs during tumor development (27) and targeting of cell cycle progression and/or machinery is effective strategy to control aberrant proliferation of cancer cell (28,29). There are two major checkpoints, G1/S and G2/M checkpoints, are known to regulate the cell cycle. The G2/M checkpoint plays...