An abundance of scientific literature exists demonstrating that oxidative stress influences the MAPK signaling pathways. This review summarizes these findings for the ERK, JNK, p38, and BMK1 pathways. For each of these different MAPK signaling pathways, the following is reviewed: the proteins involved in the signaling pathways, how oxidative stress can activate cellular signaling via these pathways, the types of oxidative stress that are known to induce activation of the different pathways, and the specific cell types in which oxidants induce MAPK responses. In addition, the functional outcome of oxidative stress-induced activation of these pathways is discussed. The purpose of this review is to provide the reader with an overall understanding and appreciation of oxidative stress-induced MAPK signaling.

No abstract

Calcium is universally required for cell growth and proliferation. Calmodulin is the main intracellular receptor for calcium. Although calcium and calmodulin are well known to be required for cell cycle regulation, the target pathways for their action remain poorly defined. Potential targets include the calcium/calmodulin-dependent kinases (CaM-K). The aim of this study was to determine the role of the CaM-Ks on cell proliferation and progress through the cell cycle in breast cancer cells. CaM-KI inhibition with either KN-93 or specific interfering RNA (siRNA) caused an arrest in the cell cycle in the human breast cancer cell line, MCF-7. This arrest occurred in the G 1 phase of the cell cycle. Supporting this finding, CaM-K inhibition using KN-93 also resulted in a reduction of cyclin D1 protein and pRb phosphorylation when cells were compared with control cultures. Furthermore, inhibition of the upstream activator of CaM-KI, CaM-KK, using siRNA also resulted in cell cycle arrest. In summary, CaM-KK and CaM-KI participate in the control of the G 0 -G 1 restriction check point of the cell cycle in human breast cancer cells. This arrest seems due to an inhibition in cyclin D1 synthesis and a reduction in pRb phosphorylation. To the best of our knowledge, this is the first time that CaM-KK has been reported to be involved in mammalian cell cycle regulation and that CaM-Ks are regulating breast cancer cell cycle. (Cancer Res 2005; 65(12): 5408-16)

NF-B is an important transcription factor that has a role in a variety of responses such as inflammation, oncogenesis, apoptosis, and viral replication. Oxidative stress is well known to induce the activation of NF-B. Cells can be exposed to either endogenously produced oxidants or oxidants produced by surrounding cells. In addition, ischemia reperfusion and certain cancer therapies such as chemotherapy and photodynamic therapy are thought to result in oxygen radical production. Because of the important role that NF-B has in multiple responses, it is critical to determine the mechanisms by which oxidative stress induces NF-B activity. We report that the calmodulin antagonist W-7 and the calcium/calmodulin-dependent (CaM) kinase inhibitors KN-93 and K252a, can block oxidative stress-induced IB phosphorylation in Jurkat T lymphocytes. Furthermore, KN-93 but not KN-92 can block hydrogen peroxide-induced Akt and IKK phosphorylation. In addition, we found that expression of a kinase-dead CaM-KIV construct in two cell lines inhibits IB phosphorylation or degradation and that expression of CaM-KIV augments hydrogen peroxide-induced IB phosphorylation and degradation. Although the CaM kinases appear to be required for this response, increases in intracellular calcium do not appear to be required. These results identify the CaM kinases as potential targets that can be used to minimize NF-B activation in response to oxidative stress.

No abstract

Oxygen radicals have diverse effects on cells. In many cases, exposure to reactive oxygen intermediates (ROI) can induce cell death. Conversely, there is also evidence that suggests oxygen radicals can activate signaling pathways that are thought to prevent cell death. In this review, the authors discuss the finding that hydrogen peroxide and ROI-generating treatments trigger the activation of the calcium/calmodulin-dependent kinases (CaM-kinases), and the potential role this activation has in preventing apoptosis. Evidence is presented that CaM-kinase activation occurs by both calcium dependent- and independent-pathways in response to ROIs. In addition, the idea is discussed that ROIs have the potential to lead to the phosphorylation of calmodulin and through this mechanism potentiate the activation of the CaM-kinases. The concept that inhibition of the CaM-kinases as a mechanism to sensitize cells to the damaging effects of ROIs is also presented. Contrasting these studies, evidence is presented that exposure of the CaM-kinases directly to hydrogen peroxide also has the apparent ability to inhibit their activity.

In this review the authors discuss the expression and activation of a family of protein kinases known as the calcium/calmodulin-dependent kinases (CaM-kinase) and the role that these kinases have in the activation of antiapoptotic signalling pathways. In addition, the authors outline a novel mechanism of activation of these kinases by oxidative stress. Founded on this novel mechanism of activation and the role that these kinases have in activating antiapoptotic signalling pathways, the authors propose that the CaM-kinases would make very good targets for sensitising cancer cells to certain therapeutic treatments. Furthermore, the authors discuss the role that these kinases have in cell transformation and in the regulation of the cell cycle. Based on these roles the authors suggest that inhibition of the CaM-kinases not only has the potential to sensitise cancer cells, but also has the potential to induce cytostasis in these cells.

Many cancer treatments induce cell death through lethal oxidative stress. Oxidative stress also induces the activation of the calcium/calmodulin-dependent kinases (CaM-Ks), CaM-KII and CaM-KIV. In turn, the CaM-Ks are known to induce the activation of antiapoptotic signaling pathways, such as Akt, ERK, and NF-kappaB in many different cell types. The aim of this study was to determine the role of CaM-Kinases in resistance to hydrogen peroxide and three oxidative stress-inducing cancer therapies in MCF-7 breast cancer cells. We found that oxidative stress induced CaM-Kinase activity in MCF-7 breast cancer cells and that CaM-K inhibition increased hydrogen peroxide-induced cell death in MCF-7 human breast cancer cells. When MCF-7 cells were treated with doxorubicin, ionizing radiation, or photodynamic therapy in the presence of a CaM-K inhibitor a greater level of cell killing was observed than when cells were treated with doxorubicin, ionizing radiation, or photodynamic therapy alone. In support of this finding, CaM-K inhibition increased hydrogen peroxide-induced apoptosis in MCF-7 cells, as determined by increased number of apoptotic cells, DNA fragmentation, and PARP cleavage. Pharmacological and molecular inhibition indicated that CaM-KII was participating in hydrogen peroxide-induced ERK phosphorylation in breast cancer cells indicating a potential mechanism by which this sensitization occurs. This is the first time that CaM-K inhibition is reported to sensitize cancer cells to reactive oxygen intermediate inducing cancer treatments.