Abstract
Bax is a key molecule in mitochondria-apoptosis pathway, however it is not always an efficient apoptosis inducer in chemotherapeutic agents-treated cancer cells. Here, we found that specific inhibition of AURKA by MLN8237-induced calpain-mediated Bax cleavage at N-terminal 33th asparagine (c-Bax) to promote apoptosis. The c-Bax, as Bax, could also efficiently located to mitochondria but c-Bax is a stronger apoptosis inducer than Bax. Morever, c-Bax-induced apoptosis could not be blocked by the canonical Bax inhibitor, Bcl-2. Further study found p27 was degraded and subsequently Bax was transformed to c-Bax through calpain. Also, p27 efficiently inhibited Bax cleavage and p27 knockdown sensitized apoptosis through Bax cleavage when cancer cells were treated with MLN8237. It is also demonstrated that the anti-apoptotic role of p27 lies its cytoplasmic localization. Finally, we found that the positive correlation between AURKA and p27 in advanced gastric cancer patients. In conclusion, we found that MNL8237 suppressed cell growth by regulating calpain-dependent Bax cleavage and p27 dysregulation in gastric cancer cells.
Highlights
Gastric cancer (GC) is a heavy burden to public health as its overall mortality ranked third in cancer-related deaths worldwide in 20121
Gastric cancer cell growth was suppressed by AURKA inhibition upon MLN8237 treatment
We determined the efficiency of MLN8237 treatment in gastric cancer cells, including AGS, SGC-7901, NCI-N87, and KATO III
Summary
Gastric cancer (GC) is a heavy burden to public health as its overall mortality ranked third in cancer-related deaths worldwide in 20121. The majority of patients suffering from gastric cancer are diagnosed at the advanced stages accompanied with malignant proliferation, dysfunction of cell cycle, and distant metastasis. The therapeutic targets and therapies for gastric cancer are limited. The molecular mechanisms accounting for the initiation and progression of GC need to be investigated to better figure out the way to cure GC. Cyclin-dependent kinase inhibitor 1B (p27) from the Cip/Kip family is a well-known cancer suppressor that. Aurora kinases, including Aurora A, B, and C, are serine/threonine kinases with major roles in mitosis and cytokinesis. At the start of S phase during mitosis, Aurora
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