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

Lin,Li; Jou,David; Wang,Yina; Ma,Haiyan; Liu,Tianshu; Fuchs,James; Li,Pui-Kai; Lü,Jiagao; Li,Chenglong; Lin,Jiayuh

doi:10.3892/ijo.2016.3728

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

Authors:
- Li Lin
- David Jou
- Yina Wang
- Haiyan Ma
- Tianshu Liu
- James Fuchs
- Pui-Kai Li
- Jiagao Lü
- Chenglong Li
- Jiayuh Lin
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Affiliations: Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, 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, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
Published online on: October 12, 2016 https://doi.org/10.3892/ijo.2016.3728
Pages: 2265-2274
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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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1	Society AC. Cancer Factor & Figures. American Cancer Society; 2015, http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf.
2	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
3	Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF and Simeone DM: Identification of pancreatic cancer stem cells. Cancer Res. 67:1030–1037. 2007. View Article : Google Scholar : PubMed/NCBI
4	Wei HJ, Yin T, Zhu Z, Shi PF, Tian Y and Wang CY: Expression of CD44, CD24 and ESA in pancreatic adenocarcinoma cell lines varies with local microenvironment. Hepatobiliary Pancreat Dis Int. 10:428–434. 2011. View Article : Google Scholar : PubMed/NCBI
5	Calò V, Migliavacca M, Bazan V, Macaluso M, Buscemi M, Gebbia N and Russo A: STAT proteins: From normal control of cellular events to tumorigenesis. J Cell Physiol. 197:157–168. 2003. View Article : Google Scholar : PubMed/NCBI
6	Germain D and Frank DA: Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. Clin Cancer Res. 13:5665–5669. 2007. View Article : Google Scholar : PubMed/NCBI
7	Turkson J and Jove R: STAT proteins: Novel molecular targets for cancer drug discovery. Oncogene. 19:6613–6626. 2000. View Article : Google Scholar
8	Zhong Z, Wen Z and Darnell JE Jr: Stat3: A STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 264:95–98. 1994. View Article : Google Scholar : PubMed/NCBI
9	Sasse J, Hemmann U, Schwartz C, Schniertshauer U, Heesel B, Landgraf C, Schneider-Mergener J, Heinrich PC and Horn F: Mutational analysis of acute-phase response factor/Stat3 activation and dimerization. Mol Cell Biol. 17:4677–4686. 1997. View Article : Google Scholar : PubMed/NCBI
10	Corvinus FM, Orth C, Moriggl R, Tsareva SA, Wagner S, Pfitzner EB, Baus D, Kaufmann R, Huber LA, Zatloukal K, et al: Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia. 7:545–555. 2005. View Article : Google Scholar : PubMed/NCBI
11	Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Nagayasu T and Sekine I: Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors. J Clin Pathol. 58:833–838. 2005. View Article : Google Scholar : PubMed/NCBI
12	Ma XT, Wang S, Ye YJ, Du RY, Cui ZR and Somsouk M: Constitutive activation of Stat3 signaling pathway in human colorectal carcinoma. World J Gastroenterol. 10:1569–1573. 2004. View Article : Google Scholar : PubMed/NCBI
13	Zhao S, Venkatasubbarao K, Lazor JW, Sperry J, Jin C, Cao L and Freeman JW: Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Res. 68:4221–4228. 2008. View Article : Google Scholar : PubMed/NCBI
14	Qiu Z, Huang C, Sun J, Qiu W, Zhang J, Li H, Jiang T, Huang K and Cao J: RNA interference-mediated signal transducers and activators of transcription 3 gene silencing inhibits invasion and metastasis of human pancreatic cancer cells. Cancer Sci. 98:1099–1106. 2007. View Article : Google Scholar : PubMed/NCBI
15	Sahu RP and Srivastava SK: The role of STAT-3 in the induction of apoptosis in pancreatic cancer cells by benzyl isothiocyanate. J Natl Cancer Inst. 101:176–193. 2009. View Article : Google Scholar : PubMed/NCBI
16	Lin L, Hutzen B, Li PK, Ball S, Zuo M, DeAngelis S, Foust E, Sobo M, Friedman L, Bhasin D, et al: A novel small molecule, LLL12, inhibits STAT3 phosphorylation and activities and exhibits potent growth-suppressive activity in human cancer cells. Neoplasia. 12:39–50. 2010. View Article : Google Scholar : PubMed/NCBI
17	Lin L, Hutzen B, Zuo M, Ball S, Deangelis S, Foust E, Pandit B, Ihnat MA, Shenoy SS, Kulp S, et al: Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells. Cancer Res. 70:2445–2454. 2010. View Article : Google Scholar : PubMed/NCBI
18	Schust J, Sperl B, Hollis A, Mayer TU and Berg T: Stattic: A small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol. 13:1235–1242. 2006. View Article : Google Scholar : PubMed/NCBI
19	Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, et al: ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 1:555–567. 2007. View Article : Google Scholar
20	Lin L, Liu A, Peng Z, Lin HJ, Li PK, Li C and Lin J: STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res. 71:7226–7237. 2011. View Article : Google Scholar : PubMed/NCBI
21	Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, Tamaki Y and Noguchi S: Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res. 15:4234–4241. 2009. View Article : Google Scholar : PubMed/NCBI
22	Kaptein A, Paillard V and Saunders M: Dominant negative stat3 mutant inhibits interleukin-6-induced Jak-STAT signal transduction. J Biol Chem. 271:5961–5964. 1996. View Article : Google Scholar : PubMed/NCBI
23	Grivennikov S and Karin M: Autocrine IL-6 signaling: A key event in tumorigenesis? Cancer Cell. 13:7–9. 2008. View Article : Google Scholar : PubMed/NCBI
24	Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM and Wicha MS: Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 6:R605–R615. 2004. View Article : Google Scholar : PubMed/NCBI
25	Tian X, Li J, Ma ZM, Zhao C, Wan DF and Wen YM: Role of hepatitis B surface antigen in the development of hepatocellular carcinoma: Regulation of lymphoid enhancer-binding factor 1. J Exp Clin Cancer Res. 28:582009. View Article : Google Scholar : PubMed/NCBI
26	Paydas S, Tanriverdi K, Yavuz S, Disel U, Sahin B and Burgut R: Survivin and aven: Two distinct antiapoptotic signals in acute leukemias. Ann Oncol. 14:1045–1050. 2003. View Article : Google Scholar : PubMed/NCBI
27	Yamaguchi H, Inokuchi K, Tarusawa M and Dan K: Mutation of bcl-x gene in non-Hodgkin's lymphoma. Am J Hematol. 69:74–76. 2002. View Article : Google Scholar : PubMed/NCBI