STAT3 as a potential therapeutic target in ALDH+ and CD44+/CD24+ stem cell-like pancreatic cancer cells

  • Int J Oncol. 2016 Dec;49(6):2265-2274. doi: 10.3892/ijo.2016.3728.
Li Lin  1 ,  David Jou  2 ,  Yina Wang  1 ,  Haiyan Ma  1 ,  Tianshu Liu  1 ,  James Fuchs  3 ,  Pui-Kai Li  3 ,  Jiagao Lü  1 ,  Chenglong Li  3 ,  Jiayuh Lin  2
Affiliations
  • 1. Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
  • 2. Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43205, USA.
  • 3. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
PMID: 27748818 DOI: 10.3892/ijo.2016.3728
Abstract

Persistent activation of signal transducers and activators of transcription 3 (STAT3) is commonly detected in many types of Cancer including pancreatic Cancer. Whether STAT3 is activated in stem cell-like pancreatic Cancer cells and the effect of STAT3 inhibition, is still unknown. Flow cytometry was used to isolate pancreatic Cancer stem-like cells which are identified by both aldehyde dehydrogenase (ALDH)-positive (ALDH+) as well as cluster of differentiation (CD) 44-positive/CD24-positive subpopulations (CD44+/CD24+). STAT3 activation and the effects of STAT3 inhibition by STAT3 inhibitors, LLL12, FLLL32, and Stattic in ALDH+ and CD44+/CD24+ cells were examined. Our results showed that ALDH+ and CD44+/CD24+ pancreatic Cancer stem-like cells expressed higher levels of phosphorylated STAT3, an active form of STAT3, compared to ALDH-negative (ALDH-) and CD44-negative/CD24-negative (CD44-/CD24-) pancreatic Cancer cells, suggesting that STAT3 is activated in pancreatic Cancer stem-like cells. Small molecular STAT3 inhibitors inhibited STAT3 phosphorylation, STAT3 downstream target gene expression, cell viability, and tumorsphere formation in ALDH+ and CD44+/CD24+ cells. Our results indicate that STAT3 is a novel therapeutic target in pancreatic Cancer stem-like cells and inhibition of activated STAT3 in these cells by STAT3 inhibitors may offer an effective treatment for pancreatic Cancer.

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