ABSTRACT
Non-SMC condensin I complex subunit D2 (NCAPD2) is one of the three non-SMC subunits in condensin I. Previous studies have shown that NCAPD2 plays an important role in the chromosome condensation and segregation. However, its role in the development of colorectal cancer (CRC) and specific molecular mechanisms still need to be further studied. Here we show that NCAPD2 inhibits autophagy and blocks autophagic flux via Ca2+/CAMKK/AMPK/mTORC1 pathway and PARP-1/SIRT1 axis. NCAPD2 acts as a tumor promoter both in vitro and in vivo. NCAPD2 knockout suppresses colorectal cancer development in AOM/DSS induced mice model. Therefore, our findings support a role for NCAPD2 in autophagy to promote CRC development and highlight NCAPD2 as a potential target for CRC therapy.
Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Kinase/genetics , Chromosomal Proteins, Non-Histone/genetics , Colorectal Neoplasms/genetics , Poly-ADP-Ribose Binding Proteins/genetics , AMP-Activated Protein Kinase Kinases/genetics , Animals , Apoptosis/genetics , Autophagy/genetics , Calcium/metabolism , Cell Line, Tumor , Colorectal Neoplasms/pathology , Humans , Mechanistic Target of Rapamycin Complex 1/genetics , Mice , Mice, Knockout , Poly (ADP-Ribose) Polymerase-1/genetics , Signal Transduction/genetics , Sirtuin 1/geneticsABSTRACT
Although baicalin, a flavonoid derived from Scutellaria baicalensis Georgi, has been reported to have anti-tumor activity in various cancers, the molecular mechanism remains imperfect. Here, we show that baicalin inhibits cell growth, migration and invasion and induces cell apoptosis by inhibiting cell cycle, viability, the epithelial-mesenchymal transition (EMT) and cellular stemness in colorectal cancer (CRC) cells. In detail, baicalin treatment in CRC cells induces cell cycle arrest in G1 phase and promotes p53-independent cell apoptosis, inhibits both endogenous and exogenous TGFß1-induced EMT of colorectal cancer cells by inhibiting TGFß/Smad pathway. Cell sphere-formation experiments show that baicalin has a strong inhibitory efficacy on the stemness of CRC cells by decreasing the marker proteins of cancer stem cell (CSC) and inhibits the formation of CSC-like cell spheres in CRC cells. In vivo experiments also identify that baicalin has an anti-tumor effect by down-regulating the levels of marker proteins of cell cycle, EMT and stemness in the orthotopic transplantation tumors of CRC cells in BALB/c nude mice. Collectively, our in vitro and in vivo results indicate that multiple inhibition of cell cycle, EMT and stemness is the real molecular mechanism of baicalin in effectively inducing cell growth inhibition and apoptosis in CRC cells.
