Alisertib induces cell cycle arrest and autophagy and suppresses epithelial-to-mesenchymal transition involving PI3K/Akt/mTOR and sirtuin 1-mediated signaling pathways in human pancreatic cancer cells

Abstract

Pancreatic cancer is the most aggressive cancer worldwide with poor response to current therapeutics. Alisertib (ALS), a potent and selective Aurora kinase A inhibitor, exhibits potent anticancer effects in preclinical and clinical studies; however, the effect and underlying mechanism of ALS in the pancreatic cancer treatment remain elusive. This study aimed to examine the effects of ALS on cell growth, autophagy, and epithelial-to-mesenchymal transition (EMT) and to delineate the possible molecular mechanisms in human pancreatic cancer PANC-1 and BxPC-3 cells. The results showed that ALS exerted potent cell growth inhibitory, pro-autophagic, and EMT-suppressing effects in PANC-1 and BxPC-3 cells. ALS remarkably arrested PANC-1 and BxPC-3 cells in G2/M phase via regulating the expression of cyclin-dependent kinases 1 and 2, cyclin B1, cyclin D1, p21 Waf1/Cip1, p27 Kip1, and p53. ALS concentration-dependently induced autophagy in PANC-1 and BxPC-3 cells, which may be attributed to the inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), p38 mitogen-activated protein kinase (p38 MAPK), and extracellular signal-regulated kinases 1 and 2 (Erk1/2) but activation of 5′-AMP-dependent kinase signaling pathways. ALS significantly inhibited EMT in PANC-1 and BxPC-3 cells with an increase in the expression of E-cadherin and a decrease in N-cadherin. In addition, ALS suppressed the expression of sirtuin 1 (Sirt1) and pre-B cell colony-enhancing factor/visfatin in both cell lines with a rise in the level of acetylated p53. These findings show that ALS induces cell cycle arrest and promotes autophagic cell death but inhibits EMT in pancreatic cancer cells with the involvement of PI3K/Akt/mTOR, p38 MAPK, Erk1/2, and Sirt1-mediated signaling pathways. Taken together, ALS may represent a promising anticancer drug for pancreatic cancer treatment. More studies are warranted to investigate other molecular targets and mechanisms and verify the efficacy and safety of ALS in the treatment of pancreatic cancer.

Analysis of Important Gene Ontology Terms and Biological Pathways Related to Pancreatic Cancer

“…The relationship between mTOR signaling pathway and pancreatic cancer has been revealed by multiple recent publications [73–75]. As a regulatory mechanism for cell proliferation, mTOR signaling pathway has been confirmed to have crosstalk with various core regulatory factors and their respective signaling pathways including MAPK , TP53 , RAS, and EGFR [76–79]. Some of such regulatory factors have also been contained in our results.…”

Molecular Mechanisms by Which a Fucus vesiculosus Extract Mediates Cell Cycle Inhibition and Cell Death in Pancreatic Cancer Cells

“…Autophagy pathways also provide a rescue mechanism by stabilizing the cell metabolism [ 22 ]. A connection between cell cycle or DNA damage and autophagy is discussed in literature, but not fully understood, yet [ 23 , 24 , 25 ]. Further in vivo experiments with Fv1 could include the combination with inhibitors of autophagy.…”

Insights into the non-mitotic functions of Aurora kinase A: more than just cell division

“…D'assoro et al showed that these features include the loss of the CD24 cell surface receptor, a mesenchimal morphology, a transcriptomic signature of 11 genes involved in EMT and metastases, together with the overexpression of the SMAD5 and SOX2 markers, which directly promote EMT and stemness. The AURKA inhibitor Alisertib was shown to block these features, arresting the cells at the G1/S checkpoint and inducing autophagy [123], and PARP-dependent apoptosis [119]. However, the molecular mechanism by which AURKA induces EMT remains to be fully disclosed.…”