APRIL Induces Tumorigenesis and Metastasis of Colorectal Cancer Cells via Activation of the PI3K/Akt Pathway

Abstract

A proliferation-inducing ligand (APRIL) is highly expressed in colorectal cancer (CRC) tissues and cell lines. However, the biological functions and precise signals elicited by APRIL in CRC have not been fully understood. Here, we used small interfering RNA to selectively deplete APRIL and to determine its tumorigenic effects in a CRC cell line SW480 both in vitro and in vivo. Knockdown of APRIL in SW480 cells was associated with modulation of cell proliferation as well as reduction of cell migration and invasion in vitro. Moreover APRIL-knockdown SW480 cells displayed markedly inhibited tumor growth and decreased metastasis to the liver in immunodeficient mice upon subcutaneous injection. Importantly, we observed that downregulation of APRIL in SW480 cells resulted in greatly decreased activity of phosphoinositide 3-kinase (PI3K)/Akt pathway. In addition, we observed that recombinant human APRIL mediated activation of the PI3K/Akt pathway in CRC cells resulting in induced expression of important cell cycle proteins and matrix metalloproteinases in a PI3K/Akt dependent manner. This was concurrent with marked cell growth viability as well as increased cell migration and invasion. Together, these compelling data suggest that APRIL-induced tumorigenesis and metastasis of CRC cells may be accomplished through activation of the PI3K/Akt pathway. These findings may lead to a better understanding of the biological effects of APRIL and may provide clues for identifying novel therapeutic and preventive molecular markers for CRC.

APRIL Induces Cisplatin Resistance in Gastric Cancer Cells via Activation of the NF-κB Pathway

“…APRIL was recently reported to activate pAKT to promote colorectal cancer cells proliferation [13], and the phosphorylated AKT could subsequently upregulate the activity of NF-κB [22]. Our results showed that APRIL overexpression in AGS cells significantly increased the phosphorylation of AKT, while silence of APRIL in SGC7901 cells significantly decreased pAKT (Fig.…”

“…High levels of APRIL mRNA were expressed in cancers of gastrointestinal tract suggesting a close interrelationship between APRIL and gastrointestinal cancers [3]. Recently, some malignant functions of APRIL have been discovered in colorectal cancer [12,13,32]. Our previous study explored that knockdown of APRIL promoted apoptosis of gastric cancer cells and down-regulated the receptor tyrosine kinases [15].…”

“…Subsequent studies demonstrated that APRIL was able to protect B cell malignant cells from drug-induced apoptosis [9,10]. High levels of APRIL mRNA are also detectable in human colorectal, hepatocellular, ovarian, bladder and head and neck carcinomas [11,12,13,14]. Furthermore, cancers of gastrointestinal tract express particularly high levels of APRIL mRNA [3].…”

CHRNA7 inhibits cell invasion and metastasis of LoVo human colorectal cancer cells through PI3K/Akt signaling

“…It is thus believed to be involved in tumor occurrence, development (35) and metastasis (36). Although activation of PI3K/Akt is more likely associated with increased MMP production and enhanced tumor cell invasion (37,38), it is also true that activation of the PI3k/Akt pathway may be associated with reduced MMP-2 and -9 production, as a result of which the metastatic potency of colon carcinoma cells is decreased (39).…”

Dendrosomal Curcumin Inhibits Metastatic Potential of Human SW480 Colon Cancer Cells through Down-regulation of Claudin1, Zeb1 and Hef1-1 Gene Expression

“…Dendrosome improves the solubility of curcumin and facilitates its uptake by cancer cells, suggesting that this polymer could open new windows to successful drug delivery in cancer therapy (Alizadeh et al, 2012;Babaei et al, 2012). In this study, given the well-known limitations of malignant colorectal cancer treatment strategies, the role of DNC on the cell metastasis and mechanisms involved in this process in SW480 cells-a highly tumorigenic and invasive colon carcinoma cell line (Trainer et al, 1988) with increased expression of genes Zeb 1, Claudin 1, Hef 1 and matrix-metalloproteinases (MMP)-1,-2,-3,-7 and -9 (Nobutomo et al, 2001;Meiko et al, 2002;Hlubek et al, 2004;Murray, 2004;Karadag et al, 2005;Tian et al, 2009;Qin et al, 2010;Amar et al, 2011;Li et al, 2011;Seo and Kim, 2011;Sanchez-Tillo et al, 2013;Wang et al, 2013;Zhao et al, 2013) and hyperactive WNT and Hedgehog signaling pathways (Korinek, 1997;Qualtrough et al, 2004), was evaluated. During carcinoma progression, cancer cells enhance their migratory and invasive capacity through down-regulation of epithelial markers, chiefly the inhibition of E-cadherin and the acquisition of a motile dedifferentiated phenotype as part of the epithelial-to mesenchymal transition.…”