Evidence indicates that hypoxia and oxidative stress can control metabolic reprogramming of cancer cells and other cells in tumor microenvironments and that the reprogrammed metabolic pathways in cancer tissue can also alter the redox balance. Thus, important steps toward developing novel cancer therapy approaches would be to identify and modulate critical biochemical nodes that are deregulated in cancer metabolism and determine if the therapeutic efficiency can be influenced by changes in redox homeostasis in cancer tissues. In this review, we will explore the molecular mechanisms responsible for the metabolic reprogramming of tumor microenvironments, the functional modulation of which may disrupt the effects of or may be disrupted by redox homeostasis modulating cancer therapy.

The tumor suppressor p53 binds prosurvival Bcl-2 family proteins such as Bcl-w and Bcl-X L to liberate Bax, which in turn exerts proapoptotic or anti-invasive functions depending on stress context. On the basis of our previous finding that p53 interacts with p21, we investigated the possible involvement of p21 in these functions. Here, we report that although p53 can bind Bcl-w alone, it requires p21 to liberate Bax to suppress cell invasion and promote cell death. p21 bound Bcl-w, forming a p53/p21/Bcl-w complex in a manner that maintained all pairwise p53/p21, p21/Bcl-w, and p53/Bcl-w interactions. This allowed Bax liberation from the complex. Accordingly, a p53 derivative incapable of binding p21 failed to mediate radiotherapy-induced tumor cell death in mice. Bcl-X L also served as a target of the cooperative action of p53 and p21. Overall, our findings indicate that the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins. We propose that the p53/p21 complex is a functional unit that acts on multiple cell components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21. Cancer Res; 77(11); 3092-100. Ó2017 AACR.

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Previous reports suggest that, in addition to its therapeutic effects, ionizing radiation (IR) increases the invasiveness of surviving cancer cells. Here, we demonstrate that this activity of IR in lung cancer cells is mediated by a signaling pathway involving p38 kinase, phosphoinositide 3-kinase, Akt, and matrix metalloproteinase (MMP-2). The invasion-promoting doses of IR also increased and reduced the levels of vimentin and E-cadherin, respectively, both of which are markers for the epithelial-mesenchymal transition (EMT). Interestingly, all of these malignant actions of IR were mimicked by the overexpression of Bcl-X L , a pro-survival member of the Bcl-2 family, in lung cancer cells. Moreover, both RNA and protein levels of Bcl-X L were elevated upon irradiation of the cells, and the prevention of this event using small-interfering RNAs of Bcl-X L reduced the ability of IR to promote invasion signals and EMT-associated events. This suggests that Bcl-X L functions as a signaling mediator of the malignant effects of IR. It was also demonstrated that IR enhances signal transducer and activator of transcription 3 (STAT3) phosphorylation, and the reduction of STAT3 levels via RNA interference prevented IR-induced Bcl-X L accumulation, and thus all the tested Bcl-X L -dependent events. Overall, the data suggest that IR induces Bcl-X L accumulation via STAT3, which then promotes cancer cell invasion and EMT-associated markers. Our findings demonstrate a novel function of Bcl-X L in cancer, and also advance our understanding of the malignant actions of IR significantly. (Cancer Sci 2010; 101: 1417-1423 A lthough ionizing radiation (IR) is widely utilized for cancer therapy, (1)(2)(3) recent studies have shown that IR also exerts undesirable effects on cancer cells. For example, the irradiation of various types of cancer cells, including glioma, (4) hepatocellular carcinoma, (5) pancreatic cancer, (6) and meningioma cells, (7) with sublethal doses of IR resulted in an increase in their invasiveness in culture. Moreover, a large number of studies using animal models have demonstrated that local radiotherapy administered to primary tumors speeds their metastatic growth in vivo, (8)(9)(10) thereby suggesting that besides its therapeutic effects, IR promotes the malignant behaviors of surviving cancer cells. This latter effect of IR is also consistent with the finding that local failure after radiotherapy increases the probability that distant metastasis will develop in cancer patients. (11) Therefore, preventing such undesirable action of IR may be an essential component of efforts to improve the efficacy of radiotherapy.In order to develop a strategy toward this objective, the mechanism by which IR promotes cancer cell invasion should be delineated. Previous studies using glioma cells have suggested that IR stimulates signaling components, such as p38 kinase, phosphoinositide 3-kinase (PI3K), and Akt, leading to matrix metalloproteinase-2 (MMP-2) expression and thus enhanced cell invasion.(4) The ability of IR to ind...

Although much is known about interleukin (IL)-1␤ and its role as a key mediator of cartilage destruction in osteoarthritis, only limited information is available on IL-1␤ signaling in chondrocyte dedifferentiation. Here, we have characterized the molecular mechanisms leading to the dedifferentiation of primary cultured articular chondrocytes by IL-1␤ treatment. IL-1␤ or lipopolysaccharide, but not phorbol 12-myristate 13-acetate, retinoic acid, or epidermal growth factor, induced nicotinamide phosphoribosyltransferase (NAMPT) expression, showing the association of inflammatory cytokines with NAMPT regulation. SIRT1, in turn, was activated NAMPT-dependently, without any alteration in the expression level. Activation or inhibition of SIRT1 oppositevely regulates IL-1␤-mediated chondrocyte dedifferentiation, suggesting this protein as a key regulator of chondrocytes phenotype. SIRT1 activation promotes induction of ERK and p38 kinase activities, but not JNK, in response to IL-1␤. Subsequently, ERK and p38 kinase activated by SIRT1 also induce SIRT1 activation, forming a positive feedback loop to sustain downstream signaling of these kinases. Moreover, we found that the SIRT1-ERK complex, but not SIRT1-p38, is engaged in IL-1␤-induced chondrocyte dedifferentiation via a Sox-9-mediated mechanism. JNK is activated by IL-1␤ and modulates dedifferentiation of chondrocytes, but this pathway is independent on NAMPT-SIRT1 signaling. Based on these findings, we propose that IL-1␤ induces dedifferentiation of articular chondrocytes by up-regulation of SIRT1 activity enhanced by both NAMPT and ERK signaling.