演題抄録

一般演題 (示説)

開催概要
開催回
第54回・2016年・横浜
 

UBE2 inhibitor NSC697923 overcomes HIF-1alpha-induced radiation resistance in colorectal cancer

演題番号 : P25-2

[筆頭演者]
Gombodorj Navchaa:1,4 
[共同演者]
Yokobori Takehiko:2、Yoshiyama Shinji:3、Kawabata Reika:3、Rokudai Susumu:2、Nishiyama Masahiko:2、Nakano Takashi:1,5

1:Gunma University Graduate School of Medicine・Department of Radiation Oncology、2:Gunma University Graduate School of Medicine・Molecular Pharmacology and Oncology、3:Gunma University Initiative for Advanced Research (GIAR)・Research Program for Omics-based Medical Science・Integrated Oncology Research、4:National Cancer Center of Mongolia・Radiation Oncology、5:Gunma University Heavy Ion Medical Center

 

Hypoxia promotes irradiation (IR) resistance and intratumoral vascularization via Hypoxia Inducible Factor 1, Alpha Subunit (HIF-1α) in colorectal cancer (CRC). We focused on the HIF-1α targeting effect by UBE2 inhibitor NSC697923 in IR-sensitive HCT116 cells expressing low HIF-1α and IR-resistance SW480 cells expressing high HIF-1α in vitro and in vivo analysis. Hypoxia significantly induced IR resistance and HIF-1α expression in both cell lines compared with a normoxic condition. NSC697923 significantly repressed HIF-1α protein level in SW480 compared with HCT116 under hypoxic condition. The combination of NSC697923 and IR strongly suppressed the cell viability in IR-resistant SW480 cells than IR-sensitive HCT116 cells. In a study on nude mice, we described the combination of NSC697923 and IR induced potent tumor inhibition effect in SW480 compared to the IR alone and NSC697923 alone. The tumor inhibition effect of the combination therapy was not enhanced in HCT116 in comparison with IR alone. The HIF-1α expression and tumor volume were suppressed by NSC697923 alone and combination of NSC697923 and IR in both cell lines mouse xenograft model.
RNA sequencing using NGS technology was performed to evaluate the suppression of HIF-1α downstream genes by NSC697923. As a result, NSC697923 could suppress the expression of representative HIF-1α downstream genes such as VEGFA, ET-1, eNOS, LDHA, and EPO. Moreover, we are investigating NSC697923 effect in intratumoral vascularization via HIF-1α activating transcription of the vascular endothelial growth factor (VEGF) gene and other several factors in different steps in angiogenesis
HIF-1α targeting therapeutic strategy by NSC697923 might overcome the hypoxia-induced IR resistance in refractory CRC patients.

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臓器別:大腸・小腸

手法別:トランスレーショナルリサーチ

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