Reference - Detail
|Author||Gombodorj N, Yokobori T, Yoshiyama S, Kawabata-Iwakawa R, Rokudai S, Horikoshi I, Nishiyama M, Nakano T.|
|Title||Inhibition of Ubiquitin-conjugating Enzyme E2 May Activate the Degradation of Hypoxia-inducible Factors and, thus, Overcome Cellular Resistance to Radiation in Colorectal Cancer.|
BACKGROUND:NSC697923, a ubiquitin-conjugating enzyme E2 (UBE2) inhibitor, was suggested as an agent to degrade hypoxia-inducible factor 1 alpha subunit (HIF1α), a key factor in radiation resistance. We attempted to clarify whether NSC697923 could overcome radiation resistance.
MATERIALS AND METHODS:Radiation resistance and expression of HIFs were evaluated in radiation-sensitive HCT116 and -resistant SW480 cells treated with or without NSC697923 and radiation under normoxia and hypoxia in vitro and in vivo. We examined NSC697923-regulated genes using RNA sequencing.
RESULTS:HIF expression significantly increased under hypoxia with an increase of cellular radiation resistance in vitro and in vivo. The therapeutic activity of NSC697923 was higher in radiation-resistant SW480 than radiation-sensitive HCT116 in vivo. Next-generation RNA sequencing revealed that NSC697923 regulated the expression of cell migration-inducing protein, hyaluronan binding (CEMIP) and apelin (APLN) genes, that are related to HIF pathways.
CONCLUSION:NSC697923 might effectively regulate HIF families, and be a promising partner with radiation to overcome resistance.
|MeSH||Animals Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors* Cell Hypoxia / drug effects Cell Hypoxia / genetics Cell Line, Tumor Cell Survival / drug effects Cisplatin / pharmacology Cisplatin / therapeutic use Colorectal Neoplasms / drug therapy Colorectal Neoplasms / genetics Colorectal Neoplasms / pathology Colorectal Neoplasms / radiotherapy Gene Expression Regulation, Neoplastic / drug effects Humans Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors* Male Mice, Inbred BALB C Mice, Nude Nitrofurans / pharmacology* Nitrofurans / therapeutic use* Radiation Tolerance / drug effects* Sulfones / pharmacology* Sulfones / therapeutic use* Tumor Burden / radiation effects Ubiquitin-Conjugating Enzymes / antagonists & inhibitors*|
|Human and Animal Cells||LoVo(RCB1639) HCT116(RCB2979)|