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

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.

journal_name

Anticancer Res

journal_title

Anticancer research

authors

Gombodorj N,Yokobori T,Yoshiyama S,Kawabata-Iwakawa R,Rokudai S,Horikoshi I,Nishiyama M,Nakano T

doi

10.21873/anticanres.11582

subject

Has Abstract

pub_date

2017-05-01 00:00:00

pages

2425-2436

issue

5

eissn

0250-7005

issn

1791-7530

pii

37/5/2425

journal_volume

37

pub_type

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