Autophagy Control by the VEGF-C/NRP-2 Axis in Cancer and its Implication for Treatment Resistance

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 1; pp. 160 - 171
• Main Authors: STANTON, Marissa J, DUTTA, Samikshan, HEYU ZHANG, POLAVARAM, Navatha S, LEONTOVICH, Alexey A, HÖNSCHEID, Pia, SINICROPE, Frank A, TINDALL, Donald J, MUDERS, Michael H, DATTA, Kaustubh
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.01.2013
• Subjects: Antineoplastic agents; Apoptosis - physiology; Autophagy - genetics; Biological and medical sciences; Blotting, Western; Cell Line, Tumor; Drug Resistance, Neoplasm - genetics; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic - genetics; Humans; Medical sciences; Microscopy, Confocal; Neoplasms - genetics; Neoplasms - metabolism; Neuropilin-2 - genetics; Neuropilin-2 - metabolism; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Real-Time Polymerase Chain Reaction; Signal Transduction - genetics; Transfection; Tumors; Vascular Endothelial Growth Factor C - genetics; Vascular Endothelial Growth Factor C - metabolism; Control; Treatment resistance; Vascular endothelium growth factor; Vascular endothelial growth factor C; Malignant tumor; Autophagy; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-11-3635

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.