Abstract 1802: Apoptosis pathway-focused gene expression profiling of a novel VEGFR2 inhibitor
Authors: Mohammad Algahtani, Khalid Alhazzani, Thiagarajan Venkatesan, Appu Rathinavelu
Journal: Cancer Research (2017)

Abstract Sprouting of the new blood vessel (angiogenesis) is fundamental to tumor growth, invasion, and metastatic dissemination. Vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, promotes cell survival via opposing apoptosis. On the other hand, antagonizing VEGF pathway suppresses endothelial cell overgrowth and promotes apoptotic signals leading to the regression of the existing vasculature and prevents neovascularization of the tumors. In this respect, a new chemical entity, code named as F16, that was developed in our institute can effectively stop VEGF-driven angiogenesis by selectively blocking VEGFR2 and the downstream signals. Our previous studies have revealed that human umbilical vein endothelial cells (HUVECs) undergo apoptosis in response to F16 treatment. However, in the present study, our main focus was on investigating the status of the signal mediators of the apoptotic pathway after treating the HUVECs with F16. This was expected to outline the intracellular sequence of events involved in triggering apoptosis following F16 treatment. For this purpose, we analyzed apoptosis pathway-focused gene expression in HUVECs using the human apoptosis RT2 profiler which contains 84 key genes involved in regulation of programmed cell death. Our experimental results clearly identified up-regulated pro-apoptotic genes in response to F16 treatment which include tumor necrosis factor -8 and -10A (TNF-8 and TNF-10A), tumor necrosis factor superfamily member 9 (TNFRSF9), FAS cell surface receptor (FAS), FAS ligand (FASLG), lymphotoxin alpha (LTA), caspase 5 (CASP5), and cytochrome c (CYCS). Moreover, a few anti-apoptotic genes were also up-regulated which include B-cell lymphoma 2 related protein A1 (BCL2A1), caspase 14 (CASP14), Bcl2 associated athanogene 3 (BAG3), and interleukin 10 (IL-10). However, anti-apoptotic genes such as Bcl-2, Bcl-2 like 10 (BCL2L10), baculoviral IAP repeat containing -3 and -6 (BIRC-3, and BIRC-6), CASP8 and FADD like apoptosis regulator (CFLAR), and insulin like growth factor 1 receptor (IGF1R) were found to be significantly downregulated. Interestingly, no changes were found in the expression of genes related to DNA damage and repair pathways such as TP53, ABL1, CIDEA, and CIDEB. This indicates that F16 may not provoke DNA damage-induced apoptosis instead, it stimulates the intrinsic or the extrinsic pathway. In conclusion, the diverse gene expressions impacting apoptosis related factors shows that F16 can induce apoptosis via potentiation of TNF- and FAS- signaling. (This research was supported by the generous funds provided by the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida) Citation Format: Mohammad Algahtani, Khalid Alhazzani, Thiagarajan Venkatesan, Appu Rathinavelu. Apoptosis pathway-focused gene expression profiling of a novel VEGFR2 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1802. doi:10.1158/1538-7445.AM2017-1802