ABSTRACT
Despite significant clinical and basic science advancements, cancer remains a devastating disease that affects people of all ages, races, and backgrounds. The pathogenesis of cancer has recently been described to result from eight biological capabilities or hallmarks and two enabling characteristics. These eight hallmarks are: deregulation of cellular energetics, avoiding immune destruction, enabling replicative immortality, inducing angiogenesis, sustaining proliferative signaling, evading growth suppressors, resisting cell death, and activating invasion and metastasis. The enabling characteristics are: genome instability and mutation and tumor-promoting inflammation. Survivin, the fourth most common transcript found in cancer cells, is a protein that is thought to be involved in the enhanced proliferation, survival, and metastasis and possibly other key hallmarks of cancer cells. Understanding how this gene is turned on and off is vitally important for attempt improving cancer management and therapy. Our work has identified a novel transcriptional regulator of survivin called Yin Yang 1 (YY1), which has been observed to activate some gene promoters and repress others and is gaining increasing interest as a target of cancer therapy. Our work shows for the first time that YY1 represses survivin transcription by physically interacting with the survivin promoter. Furthermore, YY1 appears to contribute to basal survivin transcriptional activity, indicating that disruption of its binding may in part contribute to survivin overexpression after cellular stress events including chemotherapy and radiotherapy.
Subject(s)
Neoplasms/genetics , Neovascularization, Pathologic/genetics , Survivin/genetics , YY1 Transcription Factor/genetics , Cell Movement/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Genomic Instability/genetics , Humans , Mutation , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/pathology , Neoplasm Metastasis , Neoplasms/pathology , Neovascularization, Pathologic/pathologyABSTRACT
OBJECTIVES: The inhibitor of apoptosis (IAP) proteins are critical modulators of chemotherapeutic resistance in various cancers. To address the alarming emergence of chemotherapeutic resistance in pancreatic cancer, we investigated the efficacy of the turmeric derivative curcumin in reducing IAP protein and mRNA expression resulting in pancreatic cancer cell death. METHODS: The pancreatic adenocarcinoma cell line PANC-1 was used to assess curcumin's effects in pancreatic cancer. Curcumin uptake was measured by spectral analysis and fluorescence microscopy. AlamarBlue and Trypan blue exclusion assays were used to determine PANC-1 cell viability after curcumin treatment. Visualization of PANC-1 cell death was performed using Hoffman Modulation Contrast microscopy. Western blot, and polymerase chain reaction analyses were used to evaluate curcumin's effects on IAP protein and mRNA expression. RESULTS: Curcumin enters PANC-1 cells and is ubiquitously present within the cell after treatment. Furthermore, curcumin reduces cell viability and induces morphological changes characteristic of cell death. Additionally, curcumin decreases IAP protein and mRNA expression in PANC-1 cells. CONCLUSIONS: These data demonstrate that PANC-1 cells are sensitive to curcumin treatment. Futthermore, curcumin is a potential therapeutic tool for overcoming chemotherapeutic resistance mediated by IAPs. Together, this data supports a role for curcumin as part of the therapeutic approach for the treatment of pancreatic cancer.
