The Bad, the Good, and the Ugly about Oxidative Stress
Figure 2
Proposed model of minimal completeness of cell death signaling induced by oxidative stress as a mechanistic explanation of neuronal and cancer cell demise.The neurotoxins , dopamine (DA) and its related neurotoxins (6OHDA, 5,6- and 5,7-DHT), paraquat (PQ), and rotenone (ROT) trigger a cell death subroutine in lymphocytes, a well-established model of AD and PD. This mechanism is characterized by /H2O2 generation (step 1, numbers in red), activation of the transcription factors NF-κB (step 2), p53 (step 3), and c-Jun (step 5), activation of the JNK kinase (step 4), mitochondrial depolarization (step 6), caspase-3 activation (step 7), and nuclei chromatin condensation/fragmentation (step 8). These findings may be explained by the following assumptions. H2O2 might indirectly activate NF-κB through phosphorylation of its inhibitor IκBα either by Syk (step 9, numbers in blue) or via SHIP-1 (step 10)/IKK complex pathway. H2O2 might also activate NF-κB through activation of the IKK complex by the MEKK1 protein (step 11). Once NF-κB is activated, it translocates into the nucleus and transcribes several antiapoptotic genes (step 12) and proapoptotic genes, amongst them the p53 (step 3). At this point, a vicious cycle is established. First, p53 transcribes proapoptotic genes such as Bax (step 13), contributing to the permeabilization of the outer mitochondrial membrane by antagonizing antiapoptotic proteins. Second, p53 induces prooxidant genes (e.g., p53-induced gene-3 (PIG3), proline oxidase (PO), step 14), which generate more H2O2 (step 1) and represses the transcription of antioxidant genes. H2O2 overproduction and further activation of NF-κB induce upregulation of proapoptotic genes (e.g., p53), which in turn amplify the initial H2O2-induced cell death signal (step 2–8). Mitochondrial damage allows the release of apoptogenic proteins (step 15) responsible for the formation of apoptosome and activation of caspase-3 protease. This protease in turn activates the endonucleases DFF40/CAD, by cutting the nuclease’s inhibitor DFF45/ICAD. Finally, DFF40/CAD causes nuclear chromatin fragmentation, typical of apoptosis. Alternatively, ASK1 (step 16) and MEKK1 (step 11) phosphorylate MKK4/MAPK kinase (step 17). MEKK1 kinase also phosphorylates IKK. This last kinase phosphorylates JNK1/2/SAPK (step 4), which in turn phosphorylates c-Jun, also involved in death signaling. Noticeably, vitamin C (VC) and vitamin K3 (VK3) alone or in combination induce apoptosis in Jurkat and K562 cells by a similar mechanism as described. This mechanism might provide the basis for therapeutic design strategies in AD, PD, and cancer (leukemia).
