mTORC1 inhibition and ECM–cell adhesion-independent drug resistance via PI3K–AKT and PI3K–RAS–MAPK feedback loops
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Mammalian target of rapamycin (mTOR) serine threonine kinase is the enzyme that regulates cancer cell growth by altering nutrient supplies to cancer cells. The neuropeptide (proline-rich peptide 1 (PRP-1)), galarmin, produced by the brain neurosecretory cells is a mTOR kinase inhibitor with powerful 80% antiproliferative cytostatic effect in a high-grade chondosarcoma and other mesenchymal tumors. However, the negative feedback loop of phosphatidylinositol 3 kinase–Protein kinase B (PKB), PI3K–AKT and PI3K–rat sarcoma (RAS)–mitogen-activated protein kinase (MAPK) activation is well documented for mTOR inhibitors. This study explored the involvement of those loops in drug resistance after the treatment with mTOR complex 1 (mTORC1) inhibitor, PRP-1. Multidrug resistance assay (MDR) demonstrated that this cytokine did not inhibit permeability glycoprotein-mediated MDR in chondrosarcoma. Phospho-MAPK array in human chondrosarcoma cell line treated with galarmin (10 μg/ml,) showed a strong upregulation of phosphorylated glycogen synthase kinase 3β (GSK3β) via activation of PI3K–AKT and MAPK feedback loops. Such GSK3β inactivation leads to β-catenin accumulation that entails drug resistance. The ability of cells to metastasize is reflected in their capacity to adhere to extracellular matrix and endothelium. Laminin cell adhesion assay demonstrated that PRP-1 in the same concentrations that inhibit mTOR kinase inhibited JJ012 chondrosarcoma cell adhesion. The neuropeptide did not have any effect on the expression of total focal adhesion kinase and its phosphorylated form. Thus, it was not accompanied by total HAT downregulation and total HDAC upregulation. Combinatorial treatments of PRP-1 with MAPK and PI3K/AKT inhibitors most probably will lead to full cytotoxicity overcoming drug resistance.
KeywordsChondrosarcoma mTORC1 Multidrug resistance ECM–cell adhesion
This study was supported by the Research Account of the University of Miami, Miller School of Medicine Tissue Bank.
- 2.Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118(9):3065–74.PubMedGoogle Scholar
- 7.Galoian K, Scully S, McNamara G, Flynn P, Galoyan A. Antitumorigenic effect of brain proline-rich polypeptide 1 in human chondrosarcoma. Neurochem Res Neurochem Res. 2009;34(12):2117–21.Google Scholar
- 10.Thomas Parsons J, Slack-Davis J, Tilghman R, Gregory Roberts W. Focal adhesion kinase: targeting adhesion signaling pathways for therapeutic intervention. Clin Cancer Res. 2008;627:1–14.Google Scholar
- 12.Nobili S, Landini I, Mazzei T, Mini E. Overcoming tumor multidrug resistance using drugs able to evade P-glycoprotein or to exploit its expression. Med Res Rev. 2011. doi: 10.1002/med.20239.
- 24.Burchert A, Wang Y, Cai D, von Bubnoff N, Paschka P, Müller-Brüsselbach S. O G Ottmann, J Duyster, A Hochhaus, A Neubauer. Chronic myeloid leukemia, BCR QBL studies QND. Myeloproliferative disorders. Compensatory PI3-kinase/AKT/mTor activation regulates imatinib resistance development. Leukemia. 2007;19:1774–82.CrossRefGoogle Scholar
- 25.Schwab J, Antonescu C, Boland P, Healey J, Rosenberg A, Nielsen P, Iafrate J, Delaney T, Yoon S, Choy E, Harmon D, Raskin K, Yang C, Mankin H, Springfield D, Hornicek F, Duan Z. Combination of PI3K/mTOR inhibition demonstrates efficacy in human chordoma. Anticancer Res. 2009;29(6):1867–71.PubMedGoogle Scholar
- 28.Bergin E, Levine JS, Koh JS, Lieberthal W. Mouse proximal tubular cell–cell adhesion inhibits apoptosis by a cadherin-dependent mechanism. A/J Physiol Renal Physiol. 2000;278:F758–68.Google Scholar
- 33.Cordes N, van Beuningen D. Cell adhesion to the extracellular matrix protein fibronectin modulates radiation-dependent G2 phase arrest involving integrin-linked kinase (ILK) and glycogen synthase kinase 3 beta (GSK3β) in vitro. May 6, 2003;88(9):1470–1479.Google Scholar