Abstract
Hypoxia inducible factor 1 (HIF-1) is a key player in cancer progression and an attractive target for cancer therapy. Several small molecule inhibitors of HIF-1alpha also induce a DNA damage response. However, whether or not DNA damage is required for or associated with the inhibition of HIF-1alpha protein accumulation is poorly understood. In this report we investigated the effects of distinct DNA damaging conditions on the hypoxic induction of HIF-1alpha protein in cancer cell lines. We demonstrate that in addition to topotecan (TPT), a known inhibitor of HIF-1alpha, UVC, but not other DNA damaging agents (cisplatin, ionizing radiation and doxorubicin), inhibited HIF-1alpha protein accumulation in a dose-dependent, p53-independent fashion. Low doses UVC decreased HIF-1alpha translation without affecting global protein synthesis. Inhibition of HIF-1alpha by UVC required ongoing RNA transcription, but not DNA replication. Moreover, a functional ATR was required for the activation of DNA damage-dependent responses by both UVC and TPT, but was dispensable for the inhibition of HIF-1alpha protein. Notably, unlike TPT, inhibition of HIF-1alpha protein by UVC did not require topoisomerase I, suggesting a similar yet distinct mode of action. Our data reveal that UVC is a novel signal associated with inhibition of HIF-1alpha protein accumulation, and they uncouple the DNA damage-dependent signaling pathway exerted by UVC and TPT from HIF-1alpha inhibition.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Antineoplastic Agents / pharmacology
-
Ataxia Telangiectasia Mutated Proteins
-
Cell Cycle Proteins / metabolism
-
Cell Line, Tumor
-
Cells, Cultured
-
Cisplatin / pharmacology
-
DNA Damage / drug effects
-
DNA Damage / radiation effects*
-
DNA Replication
-
DNA Topoisomerases, Type I / metabolism*
-
Dose-Response Relationship, Drug
-
Doxorubicin / pharmacology
-
Humans
-
Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
-
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
-
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
-
Immunoblotting
-
Protein Biosynthesis / drug effects
-
Protein Biosynthesis / radiation effects*
-
Protein Serine-Threonine Kinases / metabolism
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
RNA, Small Interfering / pharmacology
-
Reverse Transcriptase Polymerase Chain Reaction
-
Topotecan / pharmacology
-
Transcription, Genetic / drug effects
-
Transcription, Genetic / radiation effects
-
Tumor Cells, Cultured / drug effects
-
Tumor Cells, Cultured / radiation effects
-
Tumor Suppressor Protein p53 / genetics
-
Tumor Suppressor Protein p53 / metabolism
-
Ultraviolet Rays*
Substances
-
Antineoplastic Agents
-
Cell Cycle Proteins
-
HIF1A protein, human
-
Hypoxia-Inducible Factor 1, alpha Subunit
-
RNA, Messenger
-
RNA, Small Interfering
-
Tumor Suppressor Protein p53
-
Topotecan
-
Doxorubicin
-
ATR protein, human
-
Ataxia Telangiectasia Mutated Proteins
-
Protein Serine-Threonine Kinases
-
DNA Topoisomerases, Type I
-
Cisplatin