We have located links that may give you full text access.
Restoration of the prolyl-hydroxylase domain protein-3 oxygen-sensing mechanism is responsible for regulation of HIF2α expression and induction of sensitivity of myeloma cells to hypoxia-mediated apoptosis.
PloS One 2017
Multiple myeloma (MM) is an incurable disease of malignant plasma B-cells that infiltrate the bone marrow (BM), resulting in bone destruction, anemia, renal impairment and infections. Physiologically, the BM microenvironment is hypoxic and this promotes MM progression and contributes to resistance to chemotherapy. Since aberrant hypoxic responses may result in the selection of more aggressive tumor phenotypes, we hypothesized that targeting the hypoxia-inducible factor (HIF) pathways will be an effective anti-MM therapeutic strategy. We demonstrated that MM cells are resistant to hypoxia-mediated apoptosis in vivo and in vitro, and that constitutive expression of HIF2α contributed to this resistance. Since epigenetic silencing of the prolyl-hydroxylase-domain-3 (PHD3) enzyme responsible for the O2-dependent regulation of HIF2α is frequently observed in MM tumors, we asked if PHD3 plays a role in regulating sensitivity to hypoxia. We found that restoring PHD3 expression using a lentivirus vector or overcoming PHD3 epigenetic silencing using a demethyltransferase inhibitor, 5-Aza-2'-deoxycytidine (5-Aza-dC), rescued O2-dependent regulation of HIF2α and restored sensitivity of MM cells to hypoxia-mediated apoptosis. This provides a rationale for targeting the PHD3-mediated regulation of the adaptive cellular hypoxic response in MM and suggests that targeting the O2-sensing pathway, alone or in combination with other anti-myeloma chemotherapeutics, may have clinical efficacy.
Full text links
Related Resources
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app