Page 34 - D. Cancer biology

[D. Cancer biology-25]

Replenishment of SOCS3 suppresses angiogenesis by

negative regulation of JAK/STAT signaling

Jaehyeon Kim¹, Sukyeong Jeong¹, Shinyoung Park¹, Chohyun Kim¹, Mikyung Kim¹, Youngsil Choi¹,
Daewoong Jo¹˙*

¹R&D, Cellivery Therapeutic, Inc., Seoul 03929, Republic of Korea

Massive upregulation of cytokines and growth factors drive pathologic new vessel formation whereas physiologic

angiogenesis is more controlled. Suppressor of cytokine signaling 3 (SOCS3) is an inducible negative feedback
regulator acting downstream of janus kinase/signal transducer and activator of transduction (JAK/STAT) signaling.

Improved cell-permeable (iCP) SOCS3 has been developed by fusing sequence-optimized advanced macromolecule
transduction domain (aMTD) and SOCS3 to determine its applicability as an anti-angiogenic agent. iCP-SOCS3

reduces branching points of endothelial cells and endothelial tube length by 79% and 60% in tube formation assay.
In addition, iCP-SOCS3 suppresses aortic sprouting by 55%, comparable to the reference drug, Avastin (60%), and

decreases neovascularization in a dose-dependent manner by up to 83%, comparable to the reference, retinoic acid
(83%) in the chick embryo chorioallantoic membrane assay. Finally, in pancreatic cancer (PANC-1), hepatocellular

carcinoma (HepG2) and glioblastoma (U-87MG) cell-derived xenografts, iCP-SOCS3 reduces expression of
angiogenic markers such as VEGF, ERK and angiopoietin 1 by up to 90%. These results suggest that iCP-SOCS3,

inhibitor of JAK/STAT signaling, is an effective angiogenesis inhibitor.