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Inhibition of Ubiquitin-conjugating Enzyme E2 May Activate the Degradation of Hypoxia-inducible Factors And, Thus, Overcome Cellular Resistance to Radiation in Colorectal Cancer

Inhibition of Ubiquitin-conjugating Enzyme E2 May Activate the Degradation of Hypoxia-inducible Factors And, Thus, Overcome Cellular Resistance to Radiation in Colorectal Cancer

Navchaa Gombodorj, Takehiko Yokobori, Shinji Yoshiyama, Reika Kawabata-Iwakawa, Susumu Rokudai, Ikuko Horikoshi, Masahiko Nishiyama, Takashi Nakano

Anticancer Res. 2017 May;37(5):2425-2436.

PMID: 28476810

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP343351677	NSC697923		343351-67-7	Price

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