ABSTRACT
BACKGROUND: Differences among the top five races in Texas will be explored to determine if racial, geographic, and healthcare disparities exist in patients undergoing treatment for a primary malignant brain tumor. METHODS: Data were obtained from the Texas Cancer Registry from 1995 to 2013. SAS 9.3 (SAS Institute, Inc., Cary, NC) and SEER*Stat 8.3.2 (National Cancer Institute, Bethesda, MD) software were used to analyze death from malignant brain tumors and cause-specific survival. Survival rates were compared using Kaplan-Meier curves and Log-Rank tests. Hazard ratios were estimated using the Cox proportional hazards regression model. RESULTS: Median survival was highest among Asians at 92 months (95% CI: 72, 142) and least among Whites at 20 months (95% CI: 19, 21). Patients living in the Upper Gulf Coast region of Texas had the longest survival time at 31 months (95% CI 29-35%), while those patients in the Texas Panhandle had the shortest survival time at 18 months (95% CI 14-23%). Patients with a poverty index of 0-5% had the highest median survival time of 32 months (95% CI 29-35%), as compared to patients with a poverty index of 10-20% who had a median survival of 22 months (95% CI 21-24%). CONCLUSIONS: Ethnic minorities and higher socioeconomic class demonstrated survival advantage. White males had the worst survival of those with primary malignant brain tumors. Other significant factors affecting a patient's survival rate included geographic location, poverty index, sex, and age, thus suggesting a potential genetic and environmental influence.
ABSTRACT
BACKGROUND: It has been shown in many solid tumors that the overexpression of the pro-survival Bcl-2 family members Bcl-xL and Mcl-1 confers resistance to a variety of chemotherapeutic agents. Mcl-1 is a critical survival protein in a variety of cell lineages and is critically regulated via ubiquitination. METHODS: The Mcl-1, Bcl-xL and USP9X expression patterns in human lung and colon adenocarcinomas were evaluated via immunohistochemistry. Interaction between USP9X and Mcl-1 was demonstrated by immunoprecipitation-western blotting. The protein expression profiles of Mcl-1, Bcl-xL and USP9X in multiple cancer cell lines were determined by western blotting. Annexin-V staining and cleaved PARP western blotting were used to assay for apoptosis. The cellular toxicities after various treatments were measured via the XTT assay. RESULTS: In our current analysis of colon and lung cancer samples, we demonstrate that Mcl-1 and Bcl-xL are overexpressed and also co-exist in many tumors and that the expression levels of both genes correlate with the clinical staging. The downregulation of Mcl-1 or Bcl-xL via RNAi was found to increase the sensitivity of the tumor cells to chemotherapy. Furthermore, our analyses revealed that USP9X expression correlates with that of Mcl-1 in human cancer tissue samples. We additionally found that the USP9X inhibitor WP1130 promotes Mcl-1 degradation and increases tumor cell sensitivity to chemotherapies. Moreover, the combination of WP1130 and ABT-737, a well-documented Bcl-xL inhibitor, demonstrated a chemotherapeutic synergy and promoted apoptosis in different tumor cells. CONCLUSION: Mcl-1, Bcl-xL and USP9X overexpression are tumor survival mechanisms protective against chemotherapy. USP9X inhibition increases tumor cell sensitivity to various chemotherapeutic agents including Bcl-2/Bcl-xL inhibitors.
