Part of this research has been published in Thu et al., Oncogene. 2011.
Melanoma is a deadly malignancy which develops from melanocytes, a cell type in the skin which produces melanin. Previous research from my graduate research lab demonstrated that a transcription factor NF-kB activity is elevated in melanoma cells. However, how this activity is up-regulated in these malignant cells was unclear. My dissertation research was to understand the upstream signaling mechanisms that are likely to contribute to NF-kB activation.
I set out to explore the upstream protein kinase of the NF-kB pathway called NIK (NF-kB inducing kinase). We found that NIK expression was much higher in melanoma patient tissues and cell lines compared to the normal counterparts. This clue led us to propose that NIK fueled the growth of cancer cells. To test this idea, we experimentally reduced NIK expression levels by RNA interference. As we predicted, NIK depletion substantially attenuated the tumor growth both in culture and in mice! Along the way, we also discovered a novel connection between NIK and another cancer signaling pathway known to be active in melanoma. These findings have therapeutic values in treating melanoma since NIK is a “druggable target”.
In addition, we wanted to understand if targeting NF-kB activity is a viable approach for cancer therapy. This signaling pathway does not evolve to be the contributor of cancer cell growth: it has normal physiological functions. For example, NF-kB signaling is a master regulator of the host immune system. Thus, the question is whether targeting elevated activity in NF-kB in cancer cells will have undesirable side-effects for patients. Part of my thesis research was to understand the consequences of using NF-kB inhibitors on the host immune system as a whole and its defense against cancer.