To Study the Role of Sp1 in Cancer Drug Resistance( I )

Rationale: The accumulation of reactive oxygen species (ROS), which represent important cell death mediators, has been shown to be involved in the response to the most common types of chemotherapy, including temozolomide (TMZ) and doxorubicin. However, many stress-induced signaling pathways that are involved in drug resistance can regulate the metabolism of ROS in order to reduce cytotoxicity. Our previous study indicated that stress-activated Jun N-terminal kinase phosphorylates Sp1, a transcription factor, protecting it from degradation. Whether chemotherapy-induced stress affects Sp1 levels and functions, leading to drug resistance, remains unclear. Preliminary results: Our preliminary results indicated that Sp1 and its downstream targets are the key factors protecting GBM against anti-tumor treatment. These results include the following: (1) Sp1 was found to be upregulated in high-grade gliomas and various types of tumors; (2) TMZ caused a significant increase in Sp1, especially in TMZ-resistant glioma cells; (3) Sp1 downstream targets, such as superoxide dismutase 2 (SOD2) and cancer stemness genes, were found to be elevated, and to provide cancer cells with a higher ROS elimination ability, leading to better cancer cell survival rates after TMZ treatment. However, (4) the Sp1 inhibitor, mithramycin A, and an SOD inhibitor, diethyldithiocarbamate, reduced stemness and increased TMZ sensitivity of the resistant cancer cells. Hypothesis: We suggest that Sp1-mediated SOD2 expression and/or cancer stem cell development play critical roles in drug resistance development. Specific Aims: Based on this hypothesis, our aim is to investigate the role of Sp1 in cancer drug resistance. First, we will confirm whether Sp1 and its downstream targets are involved in drug resistance in various cancer cell types. Second, we will establish animal models in order to study Sp1-mediated drug resistance. Third, we will investigate the relationship between Sp1 and drug resistance in clinical cancer specimens. Novelty and application: This project will help us understand the role of Sp1-regulated pathway and its mechanisms in the resistance developed to anti-cancer treatments, and whether targeting Sp1 and its downstream proteins may prove to be a good therapeutic strategy, aimed at preventing cancer resistance to chemotherapy.