Carcinogenesis

About: Carcinogenesis is a research topic. Over the lifetime, 60368 publications have been published within this topic receiving 3192599 citations. The topic is also known as: oncogenesis & tumorigenesis.

Cancer Chemoprevention Mechanisms Mediated Through the Keap1–Nrf2 Pathway

Abstract: The cap'n'collar (CNC) bZIP transcription factor Nrf2 controls expression of genes for antioxidant enzymes, metal-binding proteins, drug-metabolising enzymes, drug transporters, and molecular chaperones. Many chemicals that protect against carcinogenesis induce Nrf2-target genes. These compounds are all thiol-reactive and stimulate an adaptive response to redox stress in cells. Such agents induce the expression of genes that posses an antioxidant response element (ARE) in their regulatory regions. Under normal homeostatic conditions, Nrf2 activity is restricted through a Keap1-dependent ubiquitylation by Cul3-Rbx1, which targets the CNC-bZIP transcription factor for proteasomal degradation. However, as the substrate adaptor function of Keap1 is redox-sensitive, Nrf2 protein evades ubiquitylation by Cul3-Rbx1 when cells are treated with chemopreventive agents. As a consequence, Nrf2 accumulates in the nucleus where it heterodimerizes with small Maf proteins and transactivates genes regulated through an ARE. In this review, we describe synthetic compounds and phytochemicals from edible plants that induce Nrf2-target genes. We also discuss evidence for the existence of different classes of ARE (a 16-bp 5'-TMAnnRTGABnnnGCR-3' versus an 11-bp 5'-RTGABnnnGCR-3', with or without the embedded activator protein 1-binding site 5'-TGASTCA-3'), species differences in the ARE-gene battery, and the identity of critical Cys residues in Keap1 required for de-repression of Nrf2 by chemopreventive agents.

Increased manganese superoxide dismutase expression suppresses the malignant phenotype of human melanoma cells.

Abstract: Introduction of a normal human chromosome 6 into human melanoma cell lines results in suppression of tumorigenicity. This suggests that a gene(s) on chromosome 6 controls the malignant phenotype of human melanoma. Because antioxidants can suppress the tumor-promotion phase of carcinogenesis, and because the antioxidant enzyme manganese superoxide dismutase (MnSOD) has been localized to a region of chromosome 6 frequently lost in melanomas, we have examined the effect of transfecting sense and antisense human MnSOD cDNAs into melanoma cell lines. Cell lines expressing abundant (+)-sense MnSOD-5 cDNAs significantly altered their phenotype in culture and lost their ability to form colonies in soft agar and tumors in nude mice. In contrast, the introduction of antisense MnSOD or +psv2neo had no effect on melanoma tumorigenicity. These findings indicate that stable transfection of MnSOD cDNA into melanoma cell lines exerts a biological effect that mimics that observed after introduction of an entire human chromosome 6.

P53 and radiation responses.

Abstract: Cells have evolved elaborate mechanisms (checkpoints) to monitor genomic integrity in order to ensure the high-fidelity transmission of genetic information. Cells harboring defects in checkpoint pathways respond to DNA damage improperly, which in turn may enhance the rate of cancer development. Ionizing radiation (IR) primarily leads to double-strand DNA breaks (DSBs), which activate DNA damage checkpoints to initiate signals ultimately leading to a binary decision between cell death and cell survival. TP53 has been recognized as an important checkpoint protein, functioning mainly through transcriptional control of target genes that influence multiple response pathways and leading to the diversity of responses to IR in mammalian cells. We review how the tumor suppressor P53 is involved in the complex response to IR to enforce the cell's fate to live by inducing the growth arrest coupled to DNA damage repair or to die by inducing irreversible growth arrest or apoptosis. Moreover, recent insights have emerged in our understanding of how P53 modulates radiosensitivity in tissues following IR as well as its role in sensitizing cells to chemo- and radiotherapy. The P53 pathway remains an attractive target for exploitation in the war on cancer.