ABSTRACT SUBMISSION FORM
LKI ONCOFORUM
FEBRUARY 4th 2009
Please send no later than December 1st 2008 to
Presenting author: Kris Nys
Position (graduate student or postdoc): graduate student
E-mail address:
Phone: 016330233
Title: Activation of HIF-1 signalling pathways by UVB and mild hypoxia in the development of Cutaneous Malignant Melanoma
Authors: Nys K (1), Van den Oord J (2), Michiels C (3), Van Kempen L (4), Garmyn M (5) and Agostinis P (1)
Affiliation:
1) Dept. Molecular & Cell Biology, K.U.Leuven
2) Dept. Pathology, K.U.Leuven
3) Laboratory of Biochemistry and Cellular Biology, University of Namur
4) Dept. Pathology, University Hospitals, University of Nijmegen,The Netherlands
5) Laboratory of Dermatology, K.U.Leuven
Body (max 400 words):
Cutaneous malignant melanoma represent less than 10% of all dermatological cancers but are responsible for the overwhelming majority of skin cancer-related deaths. Recent studies suggest that the mild hypoxia (1-5 %O2) of the human skin represents a tumour promoting environmental factor in melanomagenesis1. In combination with other environmental stresses, such as UVB exposure, and mutations causing defects in cell death and/or survival pathways, the physiological state of the skin could aid melanoma development by increasing adaptation to cellular stress, induce a more aggressive phenotype and also affect the notorious chemoresistance of melanoma. Since the molecular elements of the cellular response to UVB and mild hypoxia are not completely understood, we set out to investigate the signalling pathways underlying the response of human melanocytes and melanoma cells to these relevant cellular stresses. Because of their crucial involvement in UVB and hypoxia signalling, and their potential role in melanomagenesis, we focused on the role and cross-talk of Hif-1 (hypoxia inducible factor-1) and MAPKs (mitogen activated protein kinases).
Exposure of melanocytes and melanoma cell lines to UVB or mild hypoxia results in the upregulation and nuclear translocation of Hif-1α, albeit with different intensity and kinetics. Hif-1α upregulation by both stress factors involves a redox-sensitive mechanism, but only for mild hypoxia are the mitochondria-generated ROS crucially important. The transient and biphasic (eIF2α-mediated) Hif-1α upregulation following UVB is correlated with rapid activation of the p38MAPK, JNK and Akt-pathways. The selective inhibition of these kinases significantly attenuates Hif-1α accumulation in normal and cancer cells, indicating that p38MAPK, JNK and Akt are important molecular elements of the cascade linking UVB irradiation to Hif-1α stabilization. Moreover, UVB irradiation is associated with the induction of Noxa, concomitant downregulation of Bip/GRP78, and cell death, which occurs through both caspase-dependent and –independent pathways. Conversely, enhanced Hif-1α upregulation in melanoma cells and melanocytes following mild hypoxia does not involve p38MAPK or JNK-signals, and correlates with Akt activation, sustained Bip/GRP78 levels and cell survival. Moreover, mild hypoxia stimulates autophagy, which is possibly coordinated through Hif-1-dependent BNIP3 upregulation. These results indicate that UVB and mild hypoxia modulate the activity of different signalling pathways impinging on Hif-1 upregulation, and can eventually lead to cell survival or cell death, depending on the type and amount of stress. We are currently characterizing the functional role of Hif-1-dependent pathways in the response of normal melanocytes and melanoma cells to these skin microenvironmental stress factors, in order to further define their role in melanoma development.
1 Bedogni et al., 2005, Cancer Cell 8:443-54