Disruption Of Key Signaling Pathways Research Articles

Curcumin against Prostate Cancer: Current Evidence.

Cancer is a condition characterized by remarkably enhanced rates of cell proliferation paired with evasion of cell death. These deregulated cellular processes take place following genetic mutations leading to the activation of oncogenes, the loss of tumor suppressor genes, and the disruption of key signaling pathways that control and promote homeostasis. Plant extracts and plant-derived compounds have historically been utilized as medicinal remedies in different cultures due to their anti-inflammatory, antioxidant, and antimicrobial properties. Many chemotherapeutic agents used in the treatment of cancer are derived from plants, and the scientific interest in discovering plant-derived chemicals with anticancer potential continues today. Curcumin, a turmeric-derived polyphenol, has been reported to possess antiproliferative and proapoptotic properties. In the present review, we summarize all the in vitro and in vivo studies examining the effects of curcumin in prostate cancer.

Abstract NG07: Genomic and transcriptomic analysis reveals incremental disruption of key signaling pathways during melanoma evolution

Abstract Thousands of tumors have been sequenced through large-scale genomic profiling efforts, and from these studies the mutational drivers of most tumor subtypes have been catalogued. Nevertheless, the order in which these mutations occur is poorly understood. This is because most tumors are sequenced at a late stage, revealing only the aftermaths of the evolutionary processes that led to their transformation. A better understanding of tumor evolution would reveal biomarkers for progression and identify crucial steps in tumorigenesis, which could be subject to future treatments. In order to delineate the evolution of melanoma, we identified cases of melanomas that were adjacent to their intact, remnant precursors (e.g. a melanoma adjacent to a nevus from which it originated). We separately microdissected the precursor and descendent areas from these cases and performed matched DNA- and RNA- sequencing on the microdissected tissues. From these data, we were able to infer the order of genetic alterations that occur during the evolution of each melanoma and the transcriptomic changes that accompanied these mutations. In total, we analyzed 230 histopathologically distinct areas (normal, precursor, and descendent tissues) from 82 patients. Somatic alterations known to activate MAP-kinase signaling occurred at the earliest stages and continued to accumulate as individual tumors evolved, indicating that MAPK signaling ramps up during progression. TERT promoter mutations were detectable in 52% of intermediate stage lesions and 85% of melanomas, regardless of tumor thickness. Telomerase expression strongly correlated with the presence of a promoter mutation, confirming that telomerase is upregulated early during progression. The transition from the benign to the malignant state was marked by the emergence of mutations affecting genes involved in chromatin remodeling and accompanied by downregulation of genes modulated by polycomb repressive complex-2 (PRC2). Mono-allelic inactivation of G1/S checkpoint genes were occasionally found in earlier histopathologic stages, whereas bi-allelic alterations, predicted to ablate checkpoint function, occurred at or after the transition to invasive melanoma. p53- and PI3-kinase pathway mutations appeared later, only becoming evident in thicker primary melanomas. Comparisons between paired primary melanomas and metastases did not reveal oncogenic alterations specifically associated with metastatic progression. The types of somatic alterations further revealed the mutational forces that shaped each melanoma during its progression. Point mutations with signatures of UV-radiation induced DNA damage were more common in the trunks of the phylogenetic trees and tended to occur prior to the transition to invasive melanoma. In contrast, copy number alterations were more branchial and tended to occur at or after the transition to invasive melanoma. In aggregate, these patterns indicate that UV radiation is the predominant mutagen shaping melanocytic neoplasms until the transition to invasive melanoma, at which point chromosomal instability prevails. Overall, this study delineates the sequential order in which key signaling pathways are disrupted during melanoma evolution, highlighting replicative senescence, G1/S arrest, and chromatin organization as barriers that have to be overcome for the transition to melanoma, whereas amplification of MAPK signaling and inactivation of the p53 and PI3-kinase pathways are associated with the progression to more advanced primaries. Citation Format: A. Hunter Shain, Nancy M. Joseph, Richard Yu, Jamal Benhamida, Shanshan Liu, Tarl Prow, Beth Ruben, Jeffrey North, Laura Pincus, Iwei Yeh, Robert Judson, Boris C. Bastian. Genomic and transcriptomic analysis reveals incremental disruption of key signaling pathways during melanoma evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr NG07.

Genomic and Transcriptomic Analysis Reveals Incremental Disruption of Key Signaling Pathways during Melanoma Evolution

We elucidated genomic and transcriptomic changes that accompany the evolution of melanoma from pre-malignant lesions by sequencing DNA and RNA from primary melanomas and their adjacent precursors, as well as matched primary tumors and regional metastases. In total, we analyzed 230 histopathologically distinct areas of melanocytic neoplasia from 82 patients. Somatic alterations sequentially induced mitogen-activated protein kinase (MAPK) pathway activation, upregulation of telomerase, modulation of the chromatin landscape, G1/S checkpoint override, ramp-up of MAPK signaling, disruption of the p53 pathway, and activation of the PI3K pathway; no mutations were specifically associated with metastatic progression, as these pathways were perturbed during the evolution of primary melanomas. UV radiation-induced point mutations steadily increased until melanoma invasion, at which point copy-number alterations also became prevalent.

Characterization of the nasopharyngeal carcinoma methylome identifies aberrant disruption of key signaling pathways and methylated tumor suppressor genes.

Nasopharyngeal carcinoma (NPC) is a common tumor consistently associated with Epstein-Barr virus infection and prevalent in South China, including Hong Kong, and southeast Asia. Current genomic sequencing studies found only rare mutations in NPC, indicating its critical epigenetic etiology, while no epigenome exists for NPC as yet. We profiled the methylomes of NPC cell lines and primary tumors, together with normal nasopharyngeal epithelial cells, using methylated DNA immunoprecipitation (MeDIP). We observed extensive, genome-wide methylation of cellular genes. Epigenetic disruption of Wnt, MAPK, TGF-β and Hedgehog signaling pathways was detected. Methylation of Wnt signaling regulators (SFRP1, 2, 4 and 5, DACT2, DKK2 and DKK3) was frequently detected in tumor and nasal swab samples from NPC patients. Functional studies showed that these genes are bona fide tumor-suppressor genes for NPC. The NPC methylome shows a special high-degree CpG methylation epigenotype, similar to the Epstein-Barr virus-infected gastric cancer, indicating a critical epigenetic etiology for NPC pathogenesis.

Tel/PDGFRβ induces stem cell differentiation via the Ras/ERK and STAT5 signaling pathways

Fusion genes involving the platelet-derived growth factor receptor-beta (PDGFRbeta) are found in a subgroup of myeloproliferative neoplasms, with one such fusion, Tel/PDGFRbeta found in a subset of chronic myelomonocytic leukemia patients. Tel/PDGFRbeta results in constitutive activation of several signaling pathways and induces a myeloproliferative disease in mice, with signals via tyrosines 579/581 identified as being important for this phenotype. In this study, we have used a tetracycline-regulated system to express wild-type and the mutated F2 Tel/PDGFRbeta to identify the key signaling pathways, which drive Tel/PDGFRbeta-induced differentiation of embryonic stem (ES) cells. The leukemic oncogene Tel/PDGFRbeta and Tel/PDGFRbeta-F2 were inducibly expressed in ES cells and their effects on self-renewal, signal transduction, and gene expression patterns analyzed. Tel/PDGFRbeta activated several major signal transduction pathways (signal transducers and activators of transcription [STAT] 3, STAT5, mitogen-activated protein kinases, phosphatidylinositol-3 kinase) in ES cells, but only specific inhibition of the mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) or STAT5 pathways was able to significantly prevent Tel/PDGFRbeta-induced differentiation and restore ES-cell self-renewal. Inhibiting the tyrosine kinase activity of the oncogene using Gleevec or PDGFRbeta inhibitor III also substantially prevented Tel/PDGFRbeta-induced differentiation and its ability to upregulate key genes involved in myelopoiesis. Tyrosines 579/581 played a critical role in mediating signals via the Ras/ERK and STAT5 pathways, with dual targeting of the tyrosine kinase activity of Tel/PDGFRbeta and the MEK/ERK pathway completely preventing Tel/PDGFRbeta-induced differentiation. These findings suggest that targeted disruption of key signaling pathways in combination with the tyrosine kinase activity of leukemic oncogenes, such as Tel/PDGFRbeta, may result in more efficacious therapies for suppressing leukemic progression in the clinical setting.

Oxidative mechanisms of hemoglobin-based blood substitutes.

Chemically or genetically altered cell-free hemoglobin (Hb) has been developed as an oxygen carrying therapeutic. Site-directed modifications are introduced and serve to stabilize the protein molecules in a tetrameric and/or a polymeric functional form. Direct cytotoxic effects associated with cell-free Hb have been ascribed to redox reactions (involving either 1 or 2 electron steps) between the heme group and peroxides. These interactions are the basis of the pseudoperoxidase activity of Hb and can be cytotoxic when reactive species are formed at relatively high concentrations during inflammation and typically lead to cell death. Peroxides relevant to biological systems include hydrogen peroxide (H2O2), lipid hydroperoxides (LOOH), and peroxynitrite (ONOO-). Reactions between Hb and peroxides form the ferryl oxidation state of the protein, analogous to compounds I and II formed in the catalytic cycle of many peroxidase enzymes. This higher oxidation state of the protein is a potent oxidant capable of promoting oxidative damage to most classes of biological molecules. Further complications are thought to arise through the disruption of key signaling pathways resulting from alteration of or destruction of important physiological mediators.