Briefly on your first point, both endogenous (such as that caused by the mitochondrial electron transport chain) and exogenous oxidative stressors can cause DNA damage, which can lead to cancer-contributing, or cancer-initiating mutations. For example, the base-excision DNA repair pathway is principally involved in removing oxidatively damaged DNA bases so that these DNA mutations do not get fixed in the genome and rather are repaired before they can result in defective/absent protein production. I am not an expert on redox status im afraid, but hopefully somebody else can help you out with that aspect.
What type of hands on experience are you talking about? I work with mutation and oxidative stress.
hi, queen victoria, What i mean is how redox imbalences affects the growth and oxidative stress maintenance in cancer cells.
You could start by reading up on how Ras GTPases are affected by the cellular redox status. They have cysteines that can be oxidised. When the redox status of a cell is altered (ie becomes more oxidative), the cysteine residue gets oxidised. This results in faster-cycling Ras, which means that their intrinsic ability to dissociate GDP is greater. In turn, this potentially means that they are more active, which then implies that they signal more to cell-growth pathways etc.
Similarly, other proteins can be affected by the redox status of cells if they have cysteines that are accessible to reactive species.
http://www.hindawi.com/journals/jst/2012/365769/
Hope this helps.
hi, noorie, u are correct regarding the Ras and cystein redox signaling now give one example of cancer where this happens or conclusion can be drawn as a whole...
Hi, jack, what u stated will leads to apoptosis,..haaaaaaaaaaaa, but no resemblance with tumorigenesis...so, lets digout more and comeup with new solution of actual ques.
The reason you are getting such a variety of responses is that there is not a simple answer. I would suggest an article by Valko et al Int J Biochem Cell Biol. 2007;39(1):44-84. Aug 4. found at pubmed http://www.ncbi.nlm.nih.gov/pubmed/16978905. This author has several other good reviews or ROS and cancer that can be found through pubmed.
Response to ROS will depend on the concentration and location of ROS exposure (Intracellular, extracellular, mitochondrial...), cell type, stage of cell cycle, and microenvironment. ROS alter cell signalling responses, cause lipid peroxidation, DNA damage, metabolic alterations, and protein modifications. Low concentrations of ROS can stimulate transformation and cancer cell growth while higher concetrations can stimulate cell death.
It will help if you focus on the cell type you are most interested in, as there are very large differences in responses between cell types. Remember also that cell culture encourages cell transformation - so cells cultured for long periods of time stop acting like primary cells , and may have different profiles of ROS generation and responses.
How does oxidative stress play a role in the development and growth of cancer cells? What happens when we change the redox status?
The most used assumption of the role of oxidative stress, with its attendant generation of highly reactive ROS’s, is that the major cellular molecular target is DNA. While DNA is one of the major cellular target, most assume that the genomic DNA is damaged and that DNA genomic damage leads to genomic mutations and those genomic DNA mutations eventually lead to cancer. As a pioneer in discovering DNA damage and its repair or lack of , as well as one of the pioneers in developing in vitro “mutation” assays for mammalian cells, I offer an alterative interpretation of the role of oxidative stress. It comes from my work on “epigenetic chemicals”, such as TPA, TCDD, DDT, pthalates, bisphenol A, TGF-alpha, etc., all of which induce oxidative stress, but do not damage genomic DNA or induce mutations in mammalian cells ( see Trosko, J.E. and Upham, B.L. “The emperor wears no clothes in the field of carcinogen risk assessment: Ignored concepts in cancer risk assessment”. Mutagenesis 20: 81-92, 2005.). The mitochondrial DNA is most likely the target, not genomic DNA.
On the other hand, oxidative stress-induced ROS can activate intra-cellular communication signaling pathways to (a) inhibit gap junctional intercellular communication and to induce altered gene expression; and (b) which, then, alters cell behavior (e.g.,; blocks contact inhibition; induces mitogenesis; blocks differentiation and inhibits apoptosis in both the immune organ system and in the initiated epithelial and fibroblastic cells to lead to either carcinomas or sarcomas, respectively). (see Upham, B.L. and Trosko, J.E., “Carcinogenic tumor promotion, induced oxidative stress signaling, modulated gap junction function and altered gene expression”. Antioxidants & Redox Signaling 11: 297-308, 2009.)
In other words, this is what happens during tumor promotion, not tumor initiation. This tumor promotion process involves chronic inflammation. These redox-inducing agents cause immune cells to secrete various cytokines which, then, act on the “initiated” cells of the epithelial or fibroblastic tissues to cause them to clonally expand by both mitogenesis and the lack of apoptosis. ( see . Kang, K.-S. and Trosko, J.E. “Stem cells in toxicology: Fundamental biology and practical considerations”. Toxicological Sciences 120: 269-289, 2011).
Dear Dr James, nice comments, you may add up more about reduced intracellular environment and upregulation or downplay of cancer growth and promotion
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