Efficient elimination of pancreatic cancer stem cells by hedgehog/GLI inhibitor GANT61 in combination with mTOR inhibition

Molecular Cancer

Research

Ken-ichiro Kosai¹  Makoto Yoshimitsu²  Yumi Miyazaki³  Qiang Ding³  Shyuichirou Matsubara³  Koichiro Tsukasa³  Sonshin Takao⁴ 

[1] Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, 890-8520, Kagoshima, Japan;Department of Hematology and Immunology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, 890-8520, Kagoshima, Japan;Division of Cancer and Regenerative Medicine, Center for Advanced Biomedical Science and Swine Research, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, 890-8520, Kagoshima, Japan;Division of Cancer and Regenerative Medicine, Center for Advanced Biomedical Science and Swine Research, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, 890-8520, Kagoshima, Japan;Tanegashima Medical Center, 7463, 891-3198, Nishi-no-omote, Japan;

关键词: Pancreatic cancer;    Cancer stem cells;    GLI transcription factor;    GANT-61;    mTOR;    Rapamycin;   

DOI  :  10.1186/s12943-016-0534-2

 received in 2015-12-10, accepted in 2016-06-14,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundPancreatic cancer is one of the most lethal malignancies. The innovative treatments are required and now the cancer stem cells (CSCs) are expected to be an effective target for novel therapies. Therefore we investigated the significance of hedgehog (Hh) signaling in the maintenance of CSC-like properties of pancreatic cancer cells, in order to discover the key molecules controlling their unique properties.MethodsHuman pancreatic cancer cell lines, Capan-1, PANC-1, MIA PaCa-2 and Capan-1 M9 were used for our experiments in DMEM/F12 medium containing 10 % fetal bovine serum. Sphere formation assay, immunofluorescence staining, flow cytometric analysis and MTT cell viability assay were performed to investigate molecular signals and the efficacy in the treatment of pancreatic cancer cells.ResultsInhibition of the Hh pathway significantly reduced the expression of stem cell marker CD133 and sphere formation, an index of self-renewal capacity, demonstrating the suppression of CSC-like properties. Moreover, the GLI inhibitor GANT61 induced greater reduction in sphere formation and cell viability of pancreatic cancer cells than the smoothened (SMO) inhibitor cyclopamine. This suggests that GLI transcription factors, but not SMO membrane protein, are the key molecules in the Hh pathway. The treatment using GANT61 in combination with the inhibition of mTOR, which is another key molecule in pancreatic CSCs, resulted in the efficient reduction of cell viability and sphere formation of an inhibitor-resistant cell line, showing the strong efficacy and wide range applicability to pancreatic CSC-like cells.ConclusionsThus, this novel combination treatment could be useful for the control of pancreatic cancer by targeting pancreatic CSCs. This is the first report of the efficient elimination of pancreatic cancer stem-like cells by the double blockage of Hh/GLI and mTOR signaling.

【 授权许可】

CC BY   
© The Author(s). 2016