Adaptation to oxidative stress, chemoresistance, and cell survival.
ABSTRACT The discovery of some additional properties and functions of reactive oxygen species (ROS), beyond their toxic effects, provides a novel scenario for the molecular basis and cell regulation of several pathophysiologic processes. ROS are generated by redox-sensitive, prosurvival signaling pathways and function as second messengers in the transduction of several extracellular signals. A complex intracellular redox buffering network has developed to adapt and protect cells against the dangerous effects of oxidative stress. However, pathways involved in ROS-adaptive response may also play a critical role in protecting cells against cytotoxic effects of anticancer agents, thus supporting the hypothesis of a correlation between adaptation/resistance to oxidative stress and resistance to anticancer drugs. This review summarizes the main systems involved in the adaptive responses: an overview on the pathophysiologic relevance of mitochondria on redox-sensitive transcription factors and genes and main antioxidant networks in tumor cells is provided. One of the major aims is to highlight the adaptive mechanisms and their interplay in the intricate connection between oncogenic signaling, oxidative stress, and chemoresistance. Clarification of these mechanisms has tremendous application potential, in terms of developing novel molecular-targeted anticancer therapies and innovative strategies for rational combination of these agents with chemotherapeutic or tumor-specific biologic drugs.
Article: Overexpression of GRP94 in breast cancer cells resistant to oxidative stress promotes high levels of cancer cell proliferation and migration: implications for tumor recurrence.[show abstract] [hide abstract]
ABSTRACT: Targeting the altered redox status of cancer cells is emerging as an interesting approach to potentiate chemotherapy. However, to maximize the effectiveness of this strategy and define the correct chemotherapeutic associations, it is important to understand the biological consequences of chronically exposing cancer cells to reactive oxygen species (ROS). Using an H(2)O(2)-generating system, we selected a ROS-resistant MCF-7 breast cancer cell line, namely Resox cells. By exploring different survival pathways that are usually induced during oxidative stress, we identified a constitutive overexpression of the endoplasmic reticulum chaperone, GRP94, in these cells, whereas levels of its cytoplasmic homolog HSP90, or GRP78, were not modified. This overexpression was not mediated by constitutive unfolded protein response (UPR) activation. The increase in GRP94 is tightly linked to an increase in cell proliferation and migration capacities, as shown by GRP94-silencing experiments. Interestingly, we also observed that GRP94 silencing inhibits migration and proliferation of the highly aggressive MDA-MB-231 cells. By immunohistochemistry, we showed that GRP94 expression was higher in recurrent human breast cancers than in their paired primary neoplasias. Similar to the situation in the Resox cells, this increase was not associated with an increase in UPR activation in recurrent tumors. In conclusion, this study suggests that GRP94 overexpression may be a hallmark of aggressiveness and recurrence in breast cancers.Free radical biology & medicine 03/2012; 52(6):993-1002. · 5.42 Impact Factor
Article: Bilirubin augments radiation injury and leads to increased infection and mortality in mice: molecular mechanisms.[show abstract] [hide abstract]
ABSTRACT: Our earlier results demonstrated that clinically relevant concentrations of unconjugated bilirubin (UCB) possessed immunotoxic effects. Whole-body irradiation (WBI) with 1 to 6 Gy leads to acute radiation syndrome, immunosuppression, and makes the host susceptible to infection. Since hyperbilirubinemia has been shown to be associated with several types of cancer, the present studies were undertaken to evaluate the radiomodifying effects of UCB in radiation-exposed mice having elevated levels of UCB. Pretreatment of splenic lymphocytes with UCB (1-50 μM at UCB/BSA ratio <1) augmented radiation-induced DNA strand breaks, MMP loss, calcium release, and apoptosis. Combination treatment of mice with UCB (50mg/kg bw) followed by WBI (2 Gy) 0.5h later, resulted in significantly increased splenic atrophy, bone marrow aplasia, decreased counts of peritoneal exudate cells, and different splenocyte subsets such as CD3+ T, CD4+ T, CD8+ T, CD19+ B, and CD14+ macrophages as compared to either UCB or WBI treatment. Hematological studies showed that WBI-induced lymphopenia, thrombocytopenia, and neutropenia were further aggravated in the combination treatment group. UCB pretreatment of mice potentiated WBI-induced apoptosis and decreased WBI-induced loss of functional response of various immune cells leading to augmentation of immunosuppression and infection susceptibility caused by WBI. In an acute bacterial peritonitis model, UCB pretreatment of mice significantly increased WBI-induced proinflammatory cytokines, nitric oxide, and peritoneal bacterial load resulting in increased infection and death. Studies using the pharmacological inhibitor of p38MAPK demonstrated the involvement of p38MAPK activation in the inflammatory cascade of peritonitis. These findings should prove useful in understanding the potential risk to hyperbilirubinemic patients during radiotherapy and victims of acute radiation exposure in the course of radiation accidents.Free radical biology & medicine 07/2012; 53(5):1152-69. · 5.42 Impact Factor
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ABSTRACT: Conversely to normal cells, where deregulated oxidative stress drives the activation of death pathways, malignant cells exploit oxidative milieu for its advantage. Cancer cells are located in a very complex microenvironment together with stromal components that participate to enhance oxidative stress to promote tumor progression. Indeed, convincing experimental and clinical evidence underline the key role of oxidative stress in several tumor aspects thus affecting several characteristics of cancer cells. Oxidants influence the DNA mutational potential, intracellular signaling pathways controlling cell proliferation and survival and cell motility and invasiveness as well as control the reactivity of stromal components that is fundamental for cancer development and dissemination, inflammation, tissue repair, and de novo angiogenesis. This paper is focused on the role of oxidant species in the acquisition of two mandatory features for aggressive neoplastic cells, recently defined by Hanahan and Weinberg as new "hallmarks of cancer": tumor microenvironment and metabolic reprogramming of cancer cells.International Journal of Cell Biology 01/2012; 2012:762825.