Apoptosis, the cell’s natural mechanism for death, is a promising target for anticancer therapy. Both the intrinsic and extrinsic pathways use caspases to carry out apoptosis through the cleavage of hundreds of proteins. In cancer, the apoptotic pathway is typically inhibited through a wide variety of means including overexpression of antiapoptotic proteins and under-expression of proapoptotic proteins. Many of these changes cause intrinsic resistance to the most common anticancer therapy, chemotherapy. Promising new anticancer therapies are plant-derived compounds that exhibit anticancer activity through activating the apoptotic pathway.
Abstract. The Cancer is the second leading cause of death, following heart diseases (1), killing approximately eight million people (600,000 per year) and affecting nearly fourteen million (2).The rate at which cancer is emerging is only increasing as time goes on due to such factors as increased pollution, radiation, lack of exercise and a balanced diet, among other variables such as genetics (3). Anyone of these factors can lead to a mutation in the DNA of our cells like oncogenes and develop into cancer. The immortalization and sustainability of individual cells capable of reproducing at astonishing rates, overtake all the healthy functional cells, and eventually lead to death.The most common types of treatment against cancer include chemotherapy, surgery, radiation, and a combination of any of these treatments. However, there are challenges associated with the traditional treatments -non-specificity, toxicity, etc. The challenge of current drug therapy is the optimization of the pharmacological action of the drug, and the minimization of its toxic side effect. Local concentration of the drug at the cancer sites needs to be high, while at other tissues low to prevent any negative reactions. Application of nanotechnology in cancer treatment has the potential to solve these limitations. Designing nanoparticles loaded with multifunctional drugs, and functionalizing their surfaces with recognition proteins can target specific cancer cells (4, 5). The advantages of such targeting include the drug amount needed to achieve a therapeutic effect may be significantly reduced as well as the drug concentration on the cancer site can be increased without any bad effects on healthy cells (6).Several nanoparticle based drug delivery systemsnanodisks, HDL nanostructures, gold nanoparticles, and viral nanoparticles -have shown encouraging results in cancer therapy. Progress has been made in studying the biological features of cancer to enhance the use of nanoparticlesovercoming biological barriers, and recognizing cancerous tissue vs. healthy tissue. Looking forward, nanodrugs have great potential in cancer therapy due to their unique properties -minimizing toxicity to healthy cells, overcoming multidrug resistance (MDR), and overcoming poor solubility of anti-cancer drugs. 5975
Abstract. BRCA1 and BRCA2 are Breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) are found in a wide variety of organisms and help stabilize the genome. BRCA2 homologs and orthologs are found in organisms across three kingdoms: animal, plant, and fungi whereas BRCA1 homologs and orthologs are only found in animal and plant kingdoms. While not every organism possesses either or both of the genes, a vast majority do, indicating that the presence of BRCA1/2 genes dates back to 1.6 billion years ago when the three kingdoms were first diverging.Both genes are tumor suppressors and are highly involved in ensuring genome stability. BRCA1 is involved in both the checkpoint activation and in DNA repair, while BRCA2 regulates homologous recombination. BRCA1 and BRCA2 mutations are the cause of most hereditary breast cancer, and are responsible for up to 10% of all breast cancer. The risk for developing breast cancer is 80% with BRCA1 mutations and 60% with BRCA2 (1). While BRCA1 and BRCA2 are notoriously linked to an elevated risk of breast cancer, it has been found that they are also associated with an elevated risk for ovarian, pancreatic, endometrial, prostate, stomach, laryngeal, and fallopian tube cancers (2, 3). Breast cancer has been reported in other mammals including rodents, carnivores, and primates (4). This would suggest that BRCA1/2 mutations would affect functions that are unique to mammary tissue and mammals in general, however, that is not the case. The function of both of these genes results in genome stability. BRCA1/2 are both required for homologous recombination. BRCA1 is also involved in cell cycle checkpoints.Through examining BRCA1/2 in other organisms, the functional domains can be identified that assist in determining if mutations are cancer-causing. Additionally, this allows us to learn more about the function of these genes and possible cures and treatments. Years of research and investigation of various organisms for BRCA1/2 homologs has contributed to our knowledge of BRCA1/2's role in cancer and the evolution of these genes (Table I). BRCA1 and BRCA2 FunctionThe initial search for a gene responsible for hereditary breast cancer resulted in finding BRCA1 that is responsible for DNA repair and checkpoints in the cell cycle (5). Further inquires into genes susceptible to breast cancer found BRCA2 which has a role in homologous recombination (6). It has been found that homozygous mutations in either of these genes is lethal and development stops embryonically. Both BRCA1 and BRCA2 lead high-fidelity repair through homologous recombination (7). 293
Replication-coupled chromatin assembly is achieved by a network of alternate pathways containing different chromatin assembly factors and histone-modifying enzymes that coordinate deposition of nucleosomes at the replication fork. Here we describe the organization of a CAF-1-dependent pathway in Saccharomyces cerevisiae that regulates acetylation of histone H4 K16. We demonstrate factors that function in this CAF-1-dependent pathway are important for preventing establishment of silenced states at inappropriate genomic sites using a crippled HMR locus as a model, while factors specific to other assembly pathways do not. This CAF-1-dependent pathway required the cullin Rtt101p, but was functionally distinct from an alternate pathway involving Rtt101p-dependent ubiquitination of histone H3 and the chromatin assembly factor Rtt106p. A major implication from this work is that cells have the inherent ability to create different chromatin modification patterns during DNA replication via differential processing and deposition of histones by distinct chromatin assembly pathways within the network.
Pancreatic ductal adenocarcinoma (PDAC) stands to become the 2nd most deadly cancer by 2030. Over 90% of PDAC patients have oncogenic KRAS mutations with the most prevalent being KRASG12D which have proven difficult to therapeutically target. Several studies have implicated EGFR signaling as critical for PDAC tumorigenesis in KRAS mutant tumors. Consistent with these findings, the first FDA-approved targeted therapeutic for PDAC was the EGFR inhibitor, Erlotinib. However, single agent use of Erlotinib has shown minimal efficacy in the clinic suggesting that this signaling is complex and needs further interrogation. Studies have shown the serine/threonine phosphatase, Protein Phosphatase 2A (PP2A), negatively regulates several downstream targets of EGFR and KRAS. Our previous studies using small molecule activators of PP2A demonstrate a heterogeneous response to PP2A activation, with some PDAC cell lines downregulating oncogenic signals and others maintaining the oncogenic signaling. Using pharmacological activation of PP2A, as well as overexpression and knockdown studies, we have identified a novel signaling cascade in which PP2A activation leads to increased expression and secretion of EGFR ligands and EGFR activation in a subset of PDAC cell lines. Given this unique feedback mechanism, we combined EGFR inhibitors with PP2A activation and found that the combination killed more cells than either agent alone. Together, our studies identify a novel role for PP2A in regulating EGFR signaling and support the combined use of EGFR inhibitors and PP2A activators to increase efficacy of both agents. Citation Format: Claire M. Pfeffer, Sydney J. Clifford, Elizabeth G. Hoffman, Gagan K. Mall, Garima Baral, Brittany L. Allen-Petersen. PP2A activation drives alternative EGFR activation in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B078.
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