TY - JOUR
T1 - Autophagy control by the VEGF-C/NRP-2 axis in cancer and its implication for treatment resistance
AU - Stanton, Marissa J.
AU - Dutta, Samikshan
AU - Zhang, Heyu
AU - Polavaram, Navatha S.
AU - Leontovich, Alexey A.
AU - Hönscheid, Pia
AU - Sinicrope, Frank A.
AU - Tindall, Donald J.
AU - Muders, Michael H.
AU - Datta, Kaustubh
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-11-3635
DO - 10.1158/0008-5472.CAN-11-3635
M3 - Article
C2 - 23149913
AN - SCOPUS:84871980877
SN - 0008-5472
VL - 73
SP - 160
EP - 171
JO - Cancer Research
JF - Cancer Research
IS - 1
ER -