Enhancement of hypoxia-induced tumor cell death in vitro and radiation therapy in vivo by use of small interfering RNA targeted to hypoxia-inducible factor-1alpha.
Hypoxia-inducible factor-1alpha (HIF-1alpha) is an important transcriptional factor that is activated when mammalian cells experience hypoxia, a tumor microenvironmental condition that plays pivotal roles in tumor progression and treatment. In this study, we examined the idea of down-regulating HIF-1alpha in tumor cells for therapeutic gain. We show that the expression levels of HIF-1alpha can be significantly attenuated by use of the recently established small interfering RNA technology in combination with adenovirus-mediated gene transfer. Down-regulation of the HIF-1alpha protein enhanced hypoxia-mediated tumor cell apoptosis in vitro. Subcutaneous tumor growth was also prevented from cells with attenuated HIF-1alpha expression. In addition, intratumoral injection of adenovirus encoding the HIF-1alpha-targeted small interfering RNA had a small but significant effect on tumor growth when combined with ionizing radiation. Therefore, our results provide proof of HIF-1alpha as an effective target for anticancer therapy. They also suggest that an adenovirus-based small interfering RNA gene transfer approach may be a potentially effective adjuvant strategy for cancer treatment.
Zhang
Xiuwu
X
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Kon
Takashi
T
Wang
He
H
Li
Fang
F
Huang
Qian
Q
Rabbani
Zahid N
ZN
Kirkpatrick
John P
JP
Vujaskovic
Zeljko
Z
Dewhirst
Mark W
MW
Li
Chuan-Yuan
CY
D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D011878:Radiotherapy; D014157:Transcription Factors / Q000235:genetics*
D017931:DNA Primers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D014157:Transcription Factors