TY - JOUR
T1 - A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy
AU - Hsu, Tsung I.
AU - Chen, Ying Jung
AU - Hung, Chia Yang
AU - Wang, Yi-Ching
AU - Lin, Sin Jin
AU - Su, Wu-Chou
AU - Lai, Ming-Derg
AU - Kim, Sang Yong
AU - Wang, Qiang
AU - Qian, Keduo
AU - Goto, Masuo
AU - Zhao, Yu
AU - Kashiwada, Yoshiki
AU - Lee, Kuo Hsiung
AU - Chang, Wen Chang
AU - Hung, Jan-Jong
PY - 2015
Y1 - 2015
N2 - Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by KrasG12D or EGFRL858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15INK4b, p16INK4a, and p21CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer.
AB - Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by KrasG12D or EGFRL858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15INK4b, p16INK4a, and p21CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer.
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UR - http://www.scopus.com/inward/citedby.url?scp=84931097744&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.3701
DO - 10.18632/oncotarget.3701
M3 - Article
C2 - 25909174
AN - SCOPUS:84931097744
VL - 6
SP - 13671
EP - 13687
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 15
ER -