Abstract
Colorectal cancer (CRC) is one of the most common malignancies worldwide with substantial mortality and morbidity. Alisertib (ALS) is a selective Aurora kinase A (AURKA) inhibitor with unclear effect and molecular interactome on CRC. This study aimed to evaluate the molecular interactome and anticancer effect of ALS and explore the underlying mechanisms in HT29 and Caco-2 cells. ALS markedly arrested cells in G2/M phase in both cell lines, accompanied by remarkable alterations in the expression level of key cell cycle regulators. ALS induced apoptosis in HT29 and Caco-2 cells through mitochondrial and death receptor pathways. ALS also induced autophagy in HT29 and Caco-2 cells, with the suppression of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), but activation of 5′ AMP-activated protein kinase (AMPK) signaling pathways. There was a differential modulating effect of ALS on p38 MAPK signaling pathway in both cell lines. Moreover, induction or inhibition of autophagy modulated basal and ALS-induced apoptosis in both cell lines. ALS potently suppressed epithelial to mesenchymal transition (EMT) in HT29 and Caco-2 cells. Collectively, it suggests that induction of cell cycle arrest, promotion of apoptosis and autophagy, and suppression of EMT involving mitochondrial, death receptor, PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways contribute to the cancer cell killing effect of ALS on CRC cells.
Highlights
Colorectal cancer (CRC) is the third most common malignancy in male and the second most common one in female worldwide in 2012 [1]
The ratio of LC3-II/LC3-I was increased 1.8- and 1.8-fold when cells were treated with ALS at 1 and 5 μM, respectively (p < 0.01; Figure 7A,B). These results indicate that inhibition of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway and activation of AMPK and p38MAPK contribute to the autophagy-inducing effect of ALS on HT29 cells
In comparison to the control cells, there was a 1.6- and 1.9-fold increase in the expression level of beclin 1 when treated with ALS at 1 and 5 μM, respectively; and there was a 1.7, 1.4, and 1.5-fold increase in LC3-II/LC3-I ratio when treated with ALS at 0.1, 1, and 5 μM, respectively (p < 0.01; Figure 7A,B). These findings show that inhibition of PI3K/Akt/mTOR pathway, suppression of p38MAPK, and activation of AMPK contribute to the autophagy-inducing effect of ALS on Caco-2 cells
Summary
Colorectal cancer (CRC) is the third most common malignancy in male and the second most common one in female worldwide in 2012 [1]. It was estimated that about 136,830 new cases and 50,310 deaths occurred in US which renders CRC as the third leading cause of cancer related death in 2014 [2]. In China, CRC was the fifth most common cancer and the fifth leading cause of cancer death in 2011 [3]. There were 253,000 new CRC cases, 139,000 CRC deaths, and 583,000 people living with CRC (within 5 years of diagnosis) in 2012 in China [1]. The overall 5-year survival rate is up to 90% in patients with localized CRC [4]; it was only 5%–8% in patients with distant metastases in USA [5]. It is of great importance to develop new therapeutics for CRC treatment, in particular, the distant metastatic CRC
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