Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis

Abstract

In sporadic colon cancer, colon cancer stem cells (CCSCs) initiate tumorigenesis and may contribute to late disease recurrences and metastases. We previously showed that aldehyde dehydrogenase (ALDH) activity (as indicated by the ALDEFLUOR® assay) is an effective marker for highly enriching CCSCs for further evaluation. Here, we used comparative transcriptome and proteome approaches to identify signaling pathways overrepresented in the CCSC population. We found overexpression of several components of the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway, including PI3KR2, a regulatory subunit of PI3K. LY294002, a PI3K inhibitor, defined the contribution of the PI3K/Akt/mTOR signaling pathway in CCSCs. LY294002-treated CCSCs showed decreases in proliferation, sphere formation and self-renewal, in phosphorylation-dependent activation of Akt, and in expression of cyclin D1. Inhibition of PI3K in vivo reduced tumorigenicity, increased detection of cleaved caspase 3, an indicator of apoptosis, and elevated expression of the inflammatory chemokine, CXCL8. Collectively, these results indicate that PI3K/Akt/mTOR signaling controls CCSC proliferation and CCSC survival, and suggests that it would be useful to develop therapeutic agents that target this signaling pathway.

A Human Proteome Array Approach to Identifying Key Host Proteins Targeted by Toxoplasma Kinase ROP18

“…Intriguingly, we identified several MAPK pathway effectors, including MAP3K5, MAPK9, MAPK10, MAPK11, PRKCA, and p53, as the putative ROP18 substrates. In addition, three substrates, PDPK1, GSK3␤, and p53, are implicated in the PI3K/AKT pathway that are important for maintaining the cellular anti-apoptotic state (69). Moreover, host proteins FLT1 (70) and PRKRA (71) involved in apoptosis and cell growth were also identified as the ROP18 targets.…”

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

“…Similarly, the PI3K/ Akt/mTOR signaling pathway has been found to control the proliferation and survival of colon cancer stem cells (CCSC). In sporadic colon cancer, CCSC may cause recurrence and metastasis [14]. Xie et al [15] found that liver kinase B1 (LKB1) gene mutation or extracellular growth signal could activate mTORC1.…”

Dysregulated lncRNA-UCA1 contributes to the progression of gastric cancer through regulation of the PI3K-Akt-mTOR signaling pathway

“…Thus, based on the expression of key proteins in the PI3K-Akt-mTOR signaling pathway, UCA1 overexpression activated the PI3K-Akt-mTOR signaling pathway and UCA1 silencing inhibited the PI3K-Akt-mTOR signaling pathway. The PI3K-AktmTOR signaling pathway plays an important role in the carcinogenesis of common cancers [39,40]. In the present study, we showed that the dysregulated expression of UCA1 affected the expression of its key protein targets, such as p-AKT3, p-mTOR, and S6K, which are involved in the regulation of many biological processes during carcinogenesis, including cell proliferation, cell apoptosis, cell migration, and invasion.…”