Tivantinib inhibits the VEGF signaling pathway and induces apoptosis in gastric cancer cells with c-MET or VEGFA amplifi
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PRECLINICAL STUDIES
Tivantinib inhibits the VEGF signaling pathway and induces apoptosis in gastric cancer cells with c-MET or VEGFA amplification Bum Jun Kim 1 & Yoo Jin Kim 2 & Sung-Hwa Sohn 2 & Bohyun Kim 2 & Hee Jung Sul 2 & Hyeong Su Kim 3 & Dae Young Zang 2,3 Received: 3 February 2020 / Accepted: 15 April 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Tivantinib has been described as a selective inhibitor of c-Met and is being studied in various types of cancer. In this study, we evaluated the effects of tivantinib on the suppression of gastric cancer (GC) cell migration and apoptosis. We also examined the mechanism of action of tivantinib by oncogenic pathway analysis. We applied an RNA-sequencing approach in 34 GC patients to identify oncogenes that are differentially expressed in GC tissues. To examine the inhibitory effect of tivantinib on GC cells, we conducted apoptosis analysis using an annexin V-APC/PI apoptosis detection kit and trans-well migration assay with human GC cell lines. For oncogenic pathway analysis, Western blot and quantitative real-time PCR analysis were used to detect the expression of proteins and genes before and after tivantinib exposure. In the RNA-sequencing analysis of 34 GC patients, c-Met and VEGFA genes were expressed and positively correlated with each other. Cell migration and apoptosis analysis demonstrated that tivantinib induced the best inhibition effect in SNU620, MKN45 (carries VEGFB mutation), AGS, and MKN28 cells, but not in KATO III (carries VEGFB and VEGFC mutations) cells. Oncogenic pathway analysis showed that tivantinib, in addition to c-Met signaling pathway inhibition, also inhibits VEGF signaling and MYC expression in VEGFA-expressing GC cells. We found that tivantinib has anti-cancer activity not only in GC cells overexpressing c-Met but also in non-c-Met GC cells by inhibition of the VEGF signaling pathway. Keywords Tivantinib . C-met . VEGF . Gastric cancer
Introduction Gastric cancer (GC) is the fifth most common cancer in the world, and the third leading cause of cancer-related death globally [1]. In Korea, GC ranks first in cancer incidence Bum Jun Kim, Yoo Jin Kim and Sung-Hwa Sohn contributed equally to this work. Bum Jun Kim, Yoo Jin Kim and Sung-Hwa Sohn should be considered as co-first authors. * Dae Young Zang [email protected]; [email protected] 1
Division of Internal Medicine, National Army Capital Hospital, The Armed Forces Medical Command, Sungnam 13574, Republic of Korea
2
Hallym Translational Research Institute, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea
3
Division of Hematology-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea
and third in cancer mortality. Approximately 30,000 new GC cases and about 9000 GC-related deaths were reported in 2016 [2]. Despite recent advances in the genetic characterization of GC and the development of novel
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