PI3K/AKT/mTOR and sonic hedgehog pathways cooperate together to inhibit human pancreatic cancer stem cell characteristics and tumor growth
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Narinder Sharma1, Rajesh Nanta1, Jay Sharma2, Sumedha Gunewardena3, Karan P. Singh4, Sharmila Shankar5,6, Rakesh K. Srivastava1,5
1Department of Pharmacology, Toxicology and Therapeutics, and Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
2Celprogen Inc. Torrance, CA 90503, USA
3Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
4Division of Preventive Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35205, USA
5Kansas City VA Medical Center, Kansas City, MO, 66128, USA
6Department of Pathology, University of Missouri-School of Medicine, Kansas City, MO, 64108, USA
Keywords: pancreatic cancer, PI3K/AKT/mTOR, sonic hedgehog, cancer stem cell, Gli
Received: July 06, 2015 Accepted: September 22, 2015 Published: October 05, 2015
Cancer stem cells (CSCs) play major roles in cancer initiation, progression, and metastasis. It is evident from growing reports that PI3K/Akt/mTOR and Sonic Hedgehog (Shh) signaling pathways are aberrantly reactivated in pancreatic CSCs. Here, we examined the efficacy of combining NVP-LDE-225 (PI3K/mTOR inhibitor) and NVP-BEZ-235 (Smoothened inhibitor) on pancreatic CSCs characteristics, microRNA regulatory network, and tumor growth. NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting pancreatic CSC's characteristics and tumor growth in mice by acting at the level of Gli. Combination of NVP-LDE-225 and NVP-BEZ-235 inhibited self-renewal capacity of CSCs by suppressing the expression of pluripotency maintaining factors Nanog, Oct-4, Sox-2 and c-Myc, and transcription of Gli. NVP-LDE-225 co-operated with NVP-BEZ-235 to inhibit Lin28/Let7a/Kras axis in pancreatic CSCs. Furthermore, a superior interaction of these drugs was observed on spheroid formation by pancreatic CSCs isolated from Pankras/p53 mice. The combination of these drugs also showed superior effects on the expression of proteins involved in cell proliferation, survival and apoptosis. In addition, NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting EMT through modulation of cadherin, vimentin and transcription factors Snail, Slug and Zeb1. In conclusion, these data suggest that the combined inhibition of PI3K/Akt/mTOR and Shh pathways may be beneficial for the treatment of pancreatic cancer.
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