Autophagy control by the VEGF-C/NRP-2 axis in cancer and its implication for treatment resistance

Marissa J. Stanton, Samikshan Dutta, Heyu Zhang, Navatha S. Polavaram, Alexey A. Leontovich, Pia Hönscheid, Frank A. Sinicrope, Donald J. Tindall, Michael H. Muders, Kaustubh Datta

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

A major contributor to cancer mortality is recurrence and subsequent metastatic transformation following therapeutic intervention. Therefore, in order to develop new treatment modalities and improve the efficacy of current ones, it is important to understand themolecularmechanisms that promote resistance to therapy in cancer cells. One pathway contributing to therapy resistance is autophagy, a self-digestive process that can eliminate unnecessary or damaged organelles to protect cancer cells from death. We have found that the VEGF-C/NRP-2 axis is involved in the activation of autophagy, which helps cancer cell survival following treatment. Inhibition of mTOR complex 1 activity by this axis is the underlying mechanism for the activation of autophagy. Furthermore, we identified two VEGF-C/NRP-2-regulated genes, LAMP-2 and WDFY-1, that have previously been suggested to participate in autophagy and vesicular trafficking. Upregulation of WDFY-1 following VEGF-C or NRP-2 depletion contributes to cytotoxic drug-mediated cell death. Together, these data suggest a link between the VEGF-C/NRP-2 axis andcancer cell survival despite the presence of chemotherapy-induced stress. Effective targeting of this pathway may lead to the development of new cancer therapies.

Original languageEnglish (US)
Pages (from-to)160-171
Number of pages12
JournalCancer Research
Volume73
Issue number1
DOIs
StatePublished - Jan 1 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Stanton, M. J., Dutta, S., Zhang, H., Polavaram, N. S., Leontovich, A. A., Hönscheid, P., Sinicrope, F. A., Tindall, D. J., Muders, M. H., & Datta, K. (2013). Autophagy control by the VEGF-C/NRP-2 axis in cancer and its implication for treatment resistance. Cancer Research, 73(1), 160-171. https://doi.org/10.1158/0008-5472.CAN-11-3635