Protein Phosphatase 2A (PP2A) is a tumor suppressor whose function is lost in many cancers. An emerging, though counterintuitive, therapeutic approach is inhibition of PP2A to drive damaged cells through the cell cycle, sensitizing them to radiation therapy. We investigated the effects of PP2A inhibition on U251 glioblastoma cells following radiation treatment in vitro and in a xenograft mouse model in vivo. Radiation therapy alone augmented PP2A activity, though this was significantly attenuated with combination LB100 treatment. LB100 treatment yielded a radiation dose enhancement factor of 1.45 and increased the rate of post-radiation mitotic catastrophe at 72 and 96 hours. Glioblastoma cells treated with combination LB100 and radiation therapy maintained increased γ-H2AX expression at 24 hours, diminishing cellular repair of radiation-induced DNA double-strand breaks. Combination therapy significantly enhanced tumor growth delay and mouse survival and decreased p53 expression 3.68-fold, compared to radiation therapy alone. LB100 treatment effectively inhibited PP2A activity and enhanced U251 glioblastoma radiosensitivity in vitro and in vivo. Combination treatment with LB100 and radiation significantly delayed tumor growth, prolonging survival. The mechanism of radiosensitization appears to be related to increased mitotic catastrophe, decreased capacity for repair of DNA double-strand breaks, and diminished p53 DNA damage response pathway activity.
Background
Disparities in prevalence, HPV status, and mortality rates for head and neck cancer have been described between African Americans (AA) and European Americans (EA).
Methods
We studied the HPV status and gene expression profiles in 56 oropharyngeal/oral cavity tumors and 9 normal tissue samples from EA and AA patients treated in South Carolina between 2010 and 2012.
Results
Overall, 59% of tumors were HPV DNA-positive, but only 48% of those expressed E7 mRNA (HPV-active). The prevalence of HPV-active tumors was 10% in AA and 39% in EA patients. Tumors positive for HPV DNA but negative for HPV mRNA exhibited gene expression profiles distinct from those of both HPV-active and HPV-negative cancers, suggesting that HPV DNA+/RNA− tumors may constitute a unique group.
Conclusions
This study provides a direct assessment of differential expression patterns in HPV-related OPC arising from AA and EA patients, for which there is a paucity of data.
Brain metastases are a significant cause of cancer patient morbidity and mortality, yet preventative and therapeutic options remain an unmet need. The cytokine PEDF is downregulated in resected human brain metastases of breast cancer compared to primary breast tumors, suggesting that restoring its expression might limit metastatic spread. Here we show that outgrowth of large experimental brain metastases from human 231-BR or murine 4T1-BR breast cancer cells was suppressed by PEDF expression, as supported by in vitro analyses as well as direct intracranial implantation. Notably, the suppressive effects of PEDF were not only rapid but independent of the effects of this factor on angiogenesis. Paralleling its cytotoxic effects on breast cancer cells, PEDF also exerted a pro-survival effect on neurons that shielded the brain from tumor-induced damage, as indicated by a relative 3.5-fold reduction in the number of dying neurons adjacent to tumors expressing PEDF. Our findings establish that PEDF as both a metastatic suppressor and a neuroprotectant in the the brain, highlighting its role as a double agent in limiting brain metastasis and its local consequences.
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