Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis
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Sugong Chen1,*, Robert C. Fisher1,2,*, Steven Signs2, L. Alex Molina2, Anitha K. Shenoy3, Maria-Cecilia Lopez3, Henry V. Baker3, John M. Koomen4, Yi Chen4, Haley Gittleman5, Jill Barnholtz-Sloan5, Annamarie Berg2, Henry D. Appelman6 and Emina H. Huang1,2
1Department of Surgery, University of Florida, Gainesville, Florida 32610, USA
2Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA
3Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610, USA
4Molecular Oncology and Proteomics, SRB3, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
5Bioinformatics, Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA
6Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
*These authors have contributed equally to this work
Emina H. Huang, email: email@example.com
Keywords: colon cancer stem cells, ALDEFLUOR, tumorigenesis, PI3K/Akt/mTOR signaling, apoptosis
Received: February 05, 2016 Accepted: May 19, 2016 Published: June 8, 2016
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.
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