Publications by authors named "Kedar Hastak"
The development of stereotactic body radiation therapy (SBRT) has revolutionized radiation therapy for lung cancers and is an emerging treatment option for pancreatic cancers. However, there are many questions on how to optimize its use in chemoradiotherapy. The most relevant addition to radiotherapy regimens are inhibitors of DNA repair and DNA damage response pathways.
View Article and Find Full Text PDFThe protein product of the xeroderma pigmentosum group C (XPC) gene is a DNA damage recognition factor that functions early in the process of global genomic nucleotide excision repair. Regulation of XPC expression is governed in part by p53 at the transcriptional level. To identify the regulatory elements involved in the p53-dependent control of XPC expression, we performed a quantitative PCR tiling experiment using multiple regularly spaced primer pairs over an 11-kb region centered around the XPC transcriptional start site.
View Article and Find Full Text PDFThe basal-like subtype of breast cancer is characterized by a triple-negative (TN) phenotype (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2/neu negative). TN breast cancers share similar gene expression profiles and DNA repair deficiencies with BRCA1-associated breast cancers. BRCA1-mutant cells exhibit sensitivity to gemcitabine, cisplatin, and poly(ADP-ribose) polymerase (PARP) inhibition; therefore, we hypothesized that TN cancer cells may also exhibit sensitivity to these drugs.
View Article and Find Full Text PDFThe tumor suppressor protein p53 plays a key role in regulation of negative cellular growth in response to EGCG. To further explore the role of p53 signaling and elucidate the molecular mechanism, we employed colon cancer HCT116 cell line and its derivatives in which a specific transcriptional target of p53 is knocked down by homologous recombination. Cells expressing p53 and p21 accumulate in G1 upon treatment with EGCG.
View Article and Find Full Text PDFArticle Synopsis
- p53 is a crucial protein that activates cell cycle checkpoints in response to DNA damage, helping to maintain genomic stability and protect cells during DNA synthesis (S phase).
- When normal cells are treated with a compound that starves them of certain DNA precursors, they initially progress through DNA synthesis, but they soon begin to accumulate DNA damage, indicating a reversible form of injury.
- The DNA damage triggers a response that activates p53, leading to the transcription of genes that regulate crucial checkpoints in the G(1) and G(2) phases after the cells finish the initial S phase.
Article Synopsis
- p53 plays a crucial role in protecting cells from DNA damage, maintaining genomic stability, and activating checkpoints in the cell cycle when faced with various stresses, including those that impede DNA synthesis.
- In cases where DNA synthesis is inhibited by substances like N-phosphonacetyl-l-aspartate (PALA), p53 is essential for preventing cell cycle progression and limiting DNA damage, although low p53 levels can lead to cell cycle arrest in S phase instead.
- The release of macrophage inhibitory cytokine 1 (MIC-1) after PALA treatment provides significant protection against induced apoptosis in p53-null cells, suggesting that enhancing MIC-1 levels could improve the therapeutic use of PALA by reducing gut toxicity.
Article Synopsis
- Epigallocatechin-3-gallate (EGCG), found in green tea, activates the tumor suppressor p53 in prostate cancer cells, leading to cell death (apoptosis) and growth arrest.
- Research showed that p53 is essential in mediating these effects, as prostate cancer cells lacking p53 (PC3) continued to grow and did not undergo apoptosis after EGCG treatment.
- EGCG's impact involves an increase in p21 and Bax proteins, with silencing either of these proteins diminishing the drug's effectiveness, confirming that their functions are crucial for EGCG's action against prostate cancer cells.
Green tea constituent (-) epigallocatechin-3-gallate (EGCG) has shown remarkable cancer-preventive and some cancer-therapeutic effects. This is partially because of its ability to induce apoptosis in cancer cells without affecting normal cells. Previous studies from our laboratory have shown the involvement of NF-kappa B pathway in EGCG-mediated cell-cycle deregulation and apoptosis of human epidermoid carcinoma A431 cells.
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- Oral green tea polyphenols, particularly (-) epigallocatechin-3-gallate (EGCG), have been shown to inhibit prostate cancer development in mice by inducing apoptosis in cancer cells.
- EGCG triggers apoptosis through two main pathways: stabilizing the p53 protein, which increases its activity and targets, and negatively regulating NF-kappaB, leading to reduced levels of the pro-survival protein Bcl-2.
- This shift in protein balance activates caspases that ultimately promotes cell death, indicating that EGCG could be a potential chemopreventive agent against prostate cancer.