title: Autophagy control by the VEGF-C/NRP-2 axis in cancer and its implication for treatment resistance.
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 the molecular mechanisms 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 and cancer cell survival despite the presence of chemotherapy-induced stress. Effective targeting of this pathway may lead to the development of new cancer therapies.
authors.affiliation: Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Marissa J
authors.initials: MJ
authors.lastname: Stanton
authors.forename: Samikshan
authors.initials: S
authors.lastname: Dutta
authors.forename: Heyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Navatha S
authors.initials: NS
authors.lastname: Polavaram
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Leontovich
authors.forename: Pia
authors.initials: P
authors.lastname: Hönscheid
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tindall
authors.forename: Michael H
authors.initials: MH
authors.lastname: Muders
authors.forename: Kaustubh
authors.initials: K
authors.lastname: Datta
mesh_terms: D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000235:genetics*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D039943:Neuropilin-2 / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*
chemical_list: D039943:Neuropilin-2; D042582:Vascular Endothelial Growth Factor C