Abstract
Hedgehog signaling pathway plays a critical role in the initiation and development of pancreatic ductal adenocarcinoma (PDA) and represents an attractive target for PDA treatment. Lithium, a clinical mood stabilizer for mental disorders, potently inhibits the activity of glycogen synthase kinase 3β (GSK3β) that promotes the ubiquitin-dependent proteasome degradation of GLI1, an important downstream component of hedgehog signaling. Herein, we report that lithium inhibits cell proliferation, blocks G1/S cell-cycle progression, induces cell apoptosis and suppresses tumorigenic potential of PDA cells through down-regulation of the expression and activity of GLI1. Moreover, lithium synergistically enhances the anti-cancer effect of gemcitabine. These findings further our knowledge of mechanisms of action for lithium and provide a potentially new therapeutic strategy for PDA through targeting GLI1.
Highlights
Pancreatic ductal adenocarcinoma (PDA), characterized by extreme aggressiveness, poor prognosis and high lethality, stands as the fourth leading cause of cancer-related death in the United States and shows little improvement in survival over the past 30 years [1]
To further test if lithium treatment inhibits the tumorigenic potential of PDA cells, we performed colony formation assay, which is a test for oncogenic transformation in vitro
These data suggested that growth inhibition of PDA cells by lithium was at least partly due to Sphase cell cycle arrest and apoptosis
Summary
Pancreatic ductal adenocarcinoma (PDA), characterized by extreme aggressiveness, poor prognosis and high lethality, stands as the fourth leading cause of cancer-related death in the United States and shows little improvement in survival over the past 30 years [1]. PDA is reflective to current chemotherapeutic treatments as agents effective for other cancer types offer very limited survival benefit for PDA patients [2,3,4,5,6]. Surgical resection and gemcitabine chemotherapy are the main clinical treatment options for PDA patients based on the stage of diagnosis. Hedgehog signaling pathway (Hh pathway), initially discovered in Drosophila to be important for the development of fruit fly body fragmentation, is a key regulator of animal development [8,9]. This pathway in human starts with an intercellular ligand, hedgehog (HH) molecule, from autocrine and paracrine secretion. Binding of HH ligand to PTCH releases the repression of SMO by the PTCH, and transduces the extracellular signal by activating downstream GLI zinc finger transcription factors 1 (GLI1), a hallmark of the activation of Hh pathway [10,11]
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