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

Sugong Chen, Robert C. Fisher, Steven Signs, L. Alex Molina, Anitha K. Shenoy, Maria Cecilia Lopez, Henry V. Baker, John M. Koomen, Yi Chen, Haley Gittleman, Jill Barnholtz-Sloan, Annamarie Berg, Henry D. Appelman, Emina H. Huang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)50476-50488
Number of pages13
JournalOncotarget
Volume8
Issue number31
DOIs
StatePublished - Feb 7 2017
Externally publishedYes

Keywords

  • ALDEFLUOR
  • Apoptosis
  • Colon cancer stem cells
  • PI3K/Akt/mTOR signaling
  • Tumorigenesis

ASJC Scopus subject areas

  • Oncology

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