Mechanisms of CpG-ODN's Protection against UV-induced Cell Death (2005 - Present)

Investigator:  Yinsheng Wan, Providence College 
Mentor: John Marshall, Brown University

Abstract:  UV radiation from sunlight is a major etiologic factor of nonmelanoma skin cancer that occupies half of cancer in the United States and remains as a serious social and economical concern. If untreated, skin cancer can be life-threatening. While more efficient strategies against skin cancer are under development, understanding the mechanisms of how skin cancer is induced and developed upon chronic UV radiation becomes urgent. A large body of evidence indicates that epidermal growth factor receptor (EGFR) and its related cell apoptosis and cell survival pathways play an important role in the progress of pathogenesis of skin cancer upon chronic UV radiation. We and others previously reported that UV radiation induces EGFR activation. Our preliminary studies suggest that activation of p38 pathway is responsible for UV-induced cell apoptosis, whereas activation of Akt pathway protects cells from death. Further, UV radiation induces activation of mammalian target of rapamycin (mTOR) that is critical for cell survival. In addition, DNA-dependent protein kinase (DNA-PK) is found to be important for rescuing cells from apoptosis induced by UV radiation. Although the molecular mechanisms of UV-induced skin cancers are still not well understood, a number of approaches are sought to protect against UV radiation. The most attractive one is the potentially clinical usage of oligodeoxynucleotides containing CpG motif (or CpG-ODNs), which are well equipped to activate immune cells and function as adjuvants for vaccine strategy against allergy and cancer. Our previous studies have demonstrated that CpG-ODN activates Akt depending on DNA-PKcs⁶. Our preliminary data suggests that mTOR complex 1 (TORC1) is a downstream target of CpG-ODN/DNA-PK/Akt axis. Further, we show that CpG-ODN protects against UV-induced cell death. Nevertheless, the molecular mechanisms underlying the activation of cell apoptosis and survival by UV and the protective effect of CpG-ODN are still largely unknown.  Thus, we have formulated three specific aims to elucidate these issues. 1. How does p38 trigger apoptosis in response to UV radiation? 2.  How does UV induce Akt and mTORC1 activation? 3. How does CpG-ODN protect against UV-induced cell death? We are confident that our study will delineate novel cell signaling pathways through which UV induces apoptosis and CpG-ODN protects against UV-induced cell death. Further, our study will help develop better strategies for clinical management of UVB-induced skin cancer.