Radiation and inhibition of angiogenesis by canstatin synergize to induce HIF-1α–mediated tumor apoptotic switch
Claire Magnon, … , Michel Perricaudet, Martin Schlumberger
Claire Magnon, … , Michel Perricaudet, Martin Schlumberger
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1844-1855. https://doi.org/10.1172/JCI30269.
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Research Article Oncology

Radiation and inhibition of angiogenesis by canstatin synergize to induce HIF-1α–mediated tumor apoptotic switch

Abstract

Tumor radioresponsiveness depends on endothelial cell death, which leads in turn to tumor hypoxia. Radiation-induced hypoxia was recently shown to trigger tumor radioresistance by activating angiogenesis through hypoxia-inducible factor 1–regulated (HIF-1–regulated) cytokines. We show here that combining targeted radioiodide therapy with angiogenic inhibitors, such as canstatin, enhances direct tumor cell apoptosis, thereby overcoming radio-induced HIF-1–dependent tumor survival pathways in vitro and in vivo. We found that following dual therapy, HIF-1α increases the activity of the canstatin-induced αvβ5 signaling tumor apoptotic pathway and concomitantly abrogates mitotic checkpoint and tetraploidy triggered by radiation. Apoptosis in conjunction with mitotic catastrophe leads to lethal tumor damage. We discovered that HIF-1 displays a radiosensitizing activity that is highly dependent on treatment modalities by regulating key apoptotic molecular pathways. Our findings therefore support a crucial role for angiogenesis inhibitors in shifting the fate of radiation-induced HIF-1α activity from hypoxia-induced tumor radioresistance to hypoxia-induced tumor apoptosis. This study provides a basis for developing new biology-based clinically relevant strategies to improve the efficacy of radiation oncology, using HIF-1 as an ally for cancer therapy.

Authors

Claire Magnon, Paule Opolon, Marcel Ricard, Elisabeth Connault, Patrice Ardouin, Ariane Galaup, Didier Métivier, Jean-Michel Bidart, Stéphane Germain, Michel Perricaudet, Martin Schlumberger

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Figure 6

HIF-1 is the key regulator of the tumor apoptotic switch following combined therapy.

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HIF-1 is the key regulator of the tumor apoptotic switch following combi...
FACS, annexin V–FITC, and propidium iodide [PI] profiles of MDA-MB-231 cells that were viable (A); in early apoptosis with membrane integrity (B); or in late apoptosis with death following AdCanHSA infection combined or not with γ-radiation (C). (D) To assess the suppression of HIF-1α expression, Western blotting was done on noninfected or AdCanHSA-infected MDA-MB-231 cells that were transfected with random siRNA (siRNA scrambled [siScr]) or siRNA HIF-1α (siHIF). (E and F) Annexin V–FITC staining was performed on transfected MDA-MB-231 cells following AdCanHSA infection combined or not with γ-radiation. Bars represent SEM. Each experiment was done twice. *P < 0.05. (G) Schematic illustration of the role of HIF-1 in tumor response to canstatin and/or radiation. Endothelial cell death is directly triggered by both canstatin through an integrin-mediated mitochondrial apoptotic mechanism and radiation exposures through an apoptotic pathway. The resulting microvascular dysfunction induces HIF-1α expression, as a mandatory signal regulating the tumor adaptive response. HIF-1α in turn upregulates integrin-receptor expression on tumor cell surface, enhancing specifically HIF-1α signaling tumor apoptotic pathway triggered by canstatin. Moreover, HIF-1 confers the conversion of sublethal radiation damage, such as mitotic arrest and tetraploid status, into lethal lesions through aberrant mitosis in both endothelial and tumor cells. Collectively, induction of profound tumor cell death requires both canstatin-induced tumor apoptotic pathway and radiation-mediated mitotic catastrophe through an HIF-1 signaling molecular mechanism.