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Inhibition of sonic hedgehog and PI3K/Akt/mTOR pathways cooperate in suppressing survival, self-renewal and tumorigenic potential of glioblastoma-initiating cells

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Abstract

Since PI3K/Akt/mTOR and sonic hedgehog (SHH) signaling pathways are highly activated in glioblastoma-initiating cells (GICs), we examined the effects of inhibiting these pathways on GIC characteristics and tumor growth in mice. NVP-LDE-225 (inhibitor of Smoothened) inhibited the expression of Gli1, Gli2, Smoothened, Patched1, and Patched2, and induced the expression of SuFu, whereas NVP-BEZ-235 (dual inhibitor of PI3K and mTOR) inhibited the expression of p-PI3K, p-Akt, p-mTOR, and p-p70S6K. NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting the self-renewal capacity of GICs, expression of pluripotency maintaining factors (Nanog, c-Myc, Oct4, and Sox2), Musashi1, cyclin D1, and Bcl-2, and transcription and expression of Gli, and in inducing the expression of cleaved caspase-3, cleaved PARP and Bim. Additionally, NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting epithelial-mesenchymal transition. Finally, the combination of NVP-LDE-225 and NVP-BEZ-235 was superior in inhibiting tumor growth, regulating the expression of pluripotency promoting factors, stem cell markers, cell cycle, and cell proliferation, and modulating EMT compared to single agent alone. In conclusion, the combined inhibition of PI3K/Akt/mTOR and SHH pathways was superior to single pathway inhibition in suppressing glioblastoma growth by targeting GICs.

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Acknowledgements

We thank all the lab members for critical reading of the manuscript and technical help.

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Author notes

  1. Sharmila Shankar

    Present address: Southeast Louisiana Veterans Health Care System, New Orleans, LA, 70119, USA

  2. Sharmila Shankar & Rakesh K. Srivastava

    Present address: Stanley S. Scott Cancer Center, Department of Genetics, Louisiana State University Health Sciences Center, 1700 Tulane Avenue, New Orleans, LA, 70112, USA

Authors and Affiliations

  1. Ingenious e-Brain Solutions, 208 Welldone Tech Park, Gurugram, Haryana, India

    Rajesh Nanta

  2. St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA

    Anju Shrivastava

  3. Celprogen Inc., 3914 Del Amo Blvd. Suite 901, Torrance, CA, USA

    Jay Sharma

  4. Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO, USA

    Sharmila Shankar & Rakesh K. Srivastava

  5. Department of Pathology, University of Missouri-School of Medicine, Kansas City, MO, USA

    Sharmila Shankar

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  1. Rajesh Nanta
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Contributions

SS, AS, JS, and RKS conceived the ideas and designed the study. RN carried out the experiments, analyzed the data, and wrote the manuscript. All the authors have approved the manuscript.

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Correspondence to Rajesh Nanta or Rakesh K. Srivastava.

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Nanta, R., Shrivastava, A., Sharma, J. et al. Inhibition of sonic hedgehog and PI3K/Akt/mTOR pathways cooperate in suppressing survival, self-renewal and tumorigenic potential of glioblastoma-initiating cells. Mol Cell Biochem 454, 11–23 (2019). https://doi.org/10.1007/s11010-018-3448-z

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