Abstract
Mutations in the small GTPase R-Ras that promote constitutive activation of this signaling molecule have been observed in a variety of invasive cancer cell types. We previously reported that expression of an oncogenic form of R-Ras (R-Ras87L) in a cell line of cervical cancer (C33A cells) augments cell growth in vitro and tumorigenicity in vivo. Because increased tumorigenicity in vivo often precedes metastasis, we now examined whether the expression of R-Ras87L also increased the metastatic potential of C33A cells. Accelerated tumor growth was observed in athymic mice after subcutaneous injection of R-Ras87L-expressing C33A cells. In addition, increased metastasis to the liver, in immunodeficient SCID mice, was observed after intravenous injection of R-Ras87L-expressing C33A cells. Also, R-Ras87L-expressing cells presented decreased membrane expression of MHC class I molecules, and β1 integrins, but increased levels of PI 3-K and Akt activities. C33A cells expressing R-Ras87L also migrated more over collagen I in wound assays. Inhibition of the PI 3-K/Akt/mTOR pathway by pharmacological means blocked R-Ras87L-induced accelerated growth and migration over collagen I. These results suggest oncogenic R-Ras has a central role in cancer progression towards a metastatic phenotype, through the activation of the PI 3-K/Akt/mTOR signaling pathway.
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Acknowledgments
We thank Dr. Adrienne D. Cox for R-Ras constructs, Dr. Julian Downward for the active PI 3-K construct, and Dr. Martin Hemler, and Dr. Eric J. Brown for anti-integrin antibodies. We also thank Dr. Jesus Chimal for helping taking pictures of mouse livers, and Jose Alejandro Marmolejo Valencia for technical assistance. This work was supported by grant 36407-M from Consejo Nacional de Ciencia y Tecnología, Mexico, and by grant IN220703 from DGAPA, Universidad Nacional Autónoma de México, Mexico.
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Mora, N., Rosales, R. & Rosales, C. R-Ras promotes metastasis of cervical cancer epithelial cells. Cancer Immunol Immunother 56, 535–544 (2007). https://doi.org/10.1007/s00262-006-0205-z
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DOI: https://doi.org/10.1007/s00262-006-0205-z