| First Author | Yeramian A | Year | 2011 |
| Journal | Lab Invest | Volume | 91 |
| Issue | 6 | Pages | 859-71 |
| PubMed ID | 21537326 | Mgi Jnum | J:171907 |
| Mgi Id | MGI:5002389 | Doi | 10.1038/labinvest.2011.58 |
| Citation | Yeramian A, et al. (2011) Nuclear factor-kappaB2/p100 promotes endometrial carcinoma cell survival under hypoxia in a HIF-1alpha independent manner. Lab Invest 91(6):859-71 |
| abstractText | Endometrial carcinoma (EC) is a common female cancer, treated mainly by surgery and adjuvant radiotherapy. Relapse following treatment is associated with increased risk of metastases. Hypoxia, a common microenvironment in solid tumors, correlates with malignant progression, rendering tumors resistant to ionizing therapy. Hence, we assessed here the immunohistochemical expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and members of the NF-kappaB family in 82 primary EC and 10 post-radiation recurrences of EC. Post-radiation recurrences were highly hypoxic, with a higher expression of HIF-1alpha and also RelA (p65) and p52 when compared with primary EC. We next investigated the effects of hypoxia on EC cell lines. We found that EC cell lines are highly resistant to hypoxia-induced apoptosis. We thus focused on the molecular mechanisms involved in conferring hypoxic cell death resistance. We show that in addition to the classical NF-kappaB, hypoxia activates the alternative NF-kappaB pathway. To characterize the upstream kinases involved in the activation of these pathways, we used lentiviral-mediated knockdown and mouse embryonic fibroblasts lacking IKKalpha and IKKbeta kinases. Both IKKalpha and IKKbeta kinases are required for RelA (p65) and p100 accumulation, whereas p52 processing under hypoxia is IKKalpha dependent. Furthermore, Ishikawa endometrial cell line harboring either RelA (p65) or p52 short-hairpin RNA was sensitive to hypoxia-induced cell death, indicating that, in addition to the known prosurvival role of RelA (p65) under hypoxia, alternative NF-kappaB pathway also enhances hypoxic survival of EC cells. Interestingly, although HIF-1alpha controlled classical NF-kappaB activation pathway and survival under hypoxia through RelA (p65) nuclear accumulation, the alternative pathway was HIF-1alpha independent. These findings have important clinical implications for the improvement of EC prognosis before radiotherapy. |
