Vascular Normalization by Loss of Siah2 Results in Increased Chemotherapeutic Efficacy

Abstract

Tumor hypoxia is associated with resistance to antiangiogenic therapy and poor prognosis. The Siah E3 ubiquitin ligases regulate the hypoxic response pathway by modulating the turnover of the master proangiogenic transcription factor hypoxia-inducible factor-1a . In this study, we show that genetic deficiency in the Siah family member Siah2 results in vascular normalization and delayed tumor growth in an established transgenic model of aggressive breast cancer. Tumors arising in a Siah2À/À genetic background showed increased perfusion and pericyte-associated vasculature, similar to that occurring with antiangiogenic therapy. In support of the role of Siah2 in regulating levels of Hif-1a, expression of angiogenic factors was decreased in Siah2tumors. Blood vessel normalization in Siah2 À/À tumors resulted in an increased response to chemotherapy and prolonged survival. Together, our findings offer a preclinical proof of concept that targeting Siah2 is sufficient to attenuate Hif-1a-mediated angiogenesis and hypoxia signaling, thereby improving responses to chemotherapy.

Biomarkers Expression in Cervical Cancer and High Grade Squamous Intraepithelial Lesions

“…Early at the onset, tumor an-giogenesis is mediated not only by angiogenic factors but also directly by hypoxia [7][8][9]. As tumors grow larger, sustained tissue hypoxia may also cause molecular changes associated with a more malignant phenotype less sensitive to cytotoxic and/or radiotherapy treatments [10,11]. Lack of oxygen is a hallmark of solid tumor formation and constitutes an independent prognostic factor in diverse malignant tumors [12] Hypoxia-inducible factor-1 (HIF-1) is the transcriptional factor that mediates cellular response to hypoxia [13].…”

A C-Terminal Acidic Domain Regulates Degradation of the Transcriptional Coactivator Bob1

“…All animal procedures were conducted in accordance with Australian National Health and Medical Research or German regulations on the use and care of experimental animals and approved by the QIMR Berghofer Medical Research Institute Animal Experimentation Ethics Committee (P1499) or the Max Planck Institute of Immunobiology and Epigenetics Animal Ethics Committee (Re-To3). C57BL/6 Siah2 Ϫ/Ϫ (35) and wild-type mice were bred and maintained at the QIMR Berghofer as previously described (36). Spleens were removed from Siah2 wild-type and knockout mice, mashed, and strained through a 40-m mesh filter.…”

Novel Function of E3 Ubiquitin Ligase Siah2 to Regulate ROS Metabolism

“…A dominant negative Siah protein was also found to inhibit ERK signaling and cell proliferation, increase apoptosis induction, and reduce tumorigenesis of A549 human lung cancer cells, when injected into nude mice [32] . In addition, inhibition of the expression of Siah had an anti-tumorigenic effect in mouse melanoma, SW1 cells, and breast cancer cells [33] . Inhibition of the binding of Siah with the substrates through PHYL also reduced tumor growth, angiogenesis, and metastatic spread by the inactivated hypoxic response pathway [34] .…”