期刊
ONCOTARGET
卷 8, 期 31, 页码 50476-50488出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.9919
关键词
colon cancer stem cells; ALDEFLUOR; tumorigenesis; PI3K/Akt/mTOR signaling; apoptosis
资金
- UF Moffitt Research Collaborative Initiative [R01 CA142808, R01 CA157663]
- Cancer Center Support Grant [P30 CA076292]
- Moffitt Foundation
- Case Comprehensive Cancer Center Support Grant [U54 GM062119, T32 CA106493, P30 CA043703]
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 r 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.
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