Abstract 378: PHD3 dependent stabilization of β3-adrenoceptor induces HIF-1αactivation in Ewing sarcoma

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Abstract Hypoxia is a condition of oxygen deficiency which occurs in most growing solid tumors and stimulates a cascade of cell signals through a family of transcription factors named as hypoxia inducible factors (HIFs) that transactivate several regulatory genes involved in tumor proliferation. β3-adrenoceptors (β3-ARs) are involved in several hypoxic scenarios and in pathological conditions where hypoxia leads to important steps for cancer progression. Studies showed that β-AR blockade of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo. In this work we assumed that through PHD3 activity, β3-AR mediates hypoxia sensing needed for HIF-1α stabilization, thus we investigated a putative correlation between β3-AR/HIF-1α and PHD3. Data showed a similar outcome of β3-ARs and HIF-1α at short time of hypoxia, and that β3-AR antagonist, SR59230A reduced HIF-1α protein expression under hypoxia. β3-AR silencing under hypoxia revealed an evident reduction of HIF-1α protein expression that confirmed the β3-AR modulation of HIF-1α expression. SR59230A treatment strongly reduced the HIF-1α target genes as GLUT1, HK-2 and HIF-1α expression at long time treatment confirming the β3-AR modulation of HIF-1α transcriptional activity. Conversely, the HIF-1α-transcriptional inhibitor Topotecan did not affect β3-AR expression confirming that β3-AR mediates HIF-1α activation. Immunofluorescence and nuclear-cytoplasmic fragmentation showed that β3-AR co-localized with the nucleus under hypoxia, more than normoxia, and presence of both β3-AR and HIF-1α in the nucleus. Co-immunoprecipitation of β3-AR/HIF-1α revealed that under hypoxia, HIF-1α dissociates from β3-AR binding, but this process was abrogated by SR59230A. HIF-1α, released under hypoxia from the link with β3-AR, can play its transcriptional activity in the nucleus, while the binding with β3-AR blocks its transcriptional activity. Moreover, the β3-AR upregulation under hypoxia occurs trough an early inhibition of PHD3 activity that did not influence HIF-1α expression. Hypoxic PHD2 inhibition results after PHD3 leading to HIF-1α upregulation. Moreover, the blockade β3-AR by SR59230A, inhibited HIF-1α upregulation by increasing PHD2 activity. Citation Format: Amada Pasha, Laura Zocca, Francesco Carrozzo, Cristina Banella, Rachele Amato, Annalisa Tondo, Claudio Favre, Maura Calvani. PHD3 dependent stabilization of β3-adrenoceptor induces HIF-1αactivation in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 378.

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