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LPA signaling is regulated through the primary cilium: a novel target in glioblastoma

Oncogene volume 37, pages 1457–1471 (2018)Cite this article

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Abstract

The primary cilium is a ubiquitous organelle presented on most human cells. It is a crucial signaling hub for multiple pathways including growth factor and G-protein coupled receptors. Loss of primary cilia, observed in various cancers, has been shown to affect cell proliferation. Primary cilia formation is drastically decreased in glioblastoma (GBM), however, the role of cilia in normal astrocyte or glioblastoma proliferation has not been explored. Here, we report that loss of primary cilia in human astrocytes stimulates growth rate in a lysophosphatidic acid (LPA)-dependent manner. We show that lysophosphatidic acid receptor 1 (LPAR1) is accumulated in primary cilia. LPAR1 signaling through Gα12/Gαq was previously reported to be responsible for cancer cell proliferation. We found that in ciliated cells, Gα12 and Gαq are excluded from the cilium, creating a barrier against unlimited proliferation, one of the hallmarks of cancer. Upon loss of primary cilia, LPAR1 redistributes to the plasma membrane with a concomitant increase in LPAR1 association with Gα12 and Gαq. Inhibition of LPA signaling with the small molecule compound Ki16425 in deciliated highly proliferative astrocytes or glioblastoma patient-derived cells/xenografts drastically suppresses their growth both in vitro and in vivo. Moreover, Ki16425 brain delivery via PEG-PLGA nanoparticles inhibited tumor progression in an intracranial glioblastoma PDX model. Overall, our findings establish a novel mechanism by which primary cilium restricts proliferation and indicate that loss of primary cilia is sufficient to increase mitogenic signaling, and is important for the maintenance of a highly proliferative phenotype. Clinical application of LPA inhibitors may prove beneficial to restrict glioblastoma growth and ensure local control of disease.

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Acknowledgements

The authors thank Dr. Alexey Ivanov for sharing of the HMLE cDNA library and Brandon Jones for invaluable help with manuscript preparation.

Funding

Funding

This research was supported by grants R21CA208875 (E.N.P), R01CA148671 (E.N.P) from the NIH/NCI, U54GM104942 (W.J.G) from the NIGMS/NIH, WVU Cancer Institute Undergraduate Research Fellowship (C.L.G), and “Let the Journey Begin” fund established by Erin Dunmire, WVU Cancer Institute. Andrey Bobko is supported by startup funding from WVCTSI. Naira V. Margaryan is supported by U54GM104942 from WVCTSI. West Virginia University Microscope Imaging Facility is supported by the WVU Cancer Institute and NIH grants P20RR016440, P20 RR016477 and P30RR032138/P30GM103488.

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Authors and Affiliations

  1. WVU Cancer Institute, West Virginia University School of Medicine, Morgantown, WV, USA

    Yuriy V. Loskutov, Caryn L. Griffin, Kristina M. Marinak & Elena N. Pugacheva

  2. Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV, USA

    Andrey Bobko, Naira V. Margaryan & Elena N. Pugacheva

  3. Department of Pharmaceutical Sciences, West Virginia University School of Medicine, Morgantown, WV, USA

    Werner J. Geldenhuys

  4. Mayo Clinic, Rochester, MN, USA

    Jann N. Sarkaria

  5. Department of Radiation Oncology, West Virginia University School of Medicine, Morgantown, WV, USA

    Elena N. Pugacheva

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Loskutov, Y.V., Griffin, C.L., Marinak, K.M. et al. LPA signaling is regulated through the primary cilium: a novel target in glioblastoma. Oncogene 37, 1457–1471 (2018). https://doi.org/10.1038/s41388-017-0049-3

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