Tumor cell dormancy induced by p38(SAPK) and ER-stress signaling - An adaptive advantage for metastatic cells?

Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, University at Albany, State University of New York, Rensselaer, NY 12144-3456, USA.
Cancer biology & therapy (Impact Factor: 3.07). 08/2006; 5(7):729-35. DOI: 10.4161/cbt.5.7.2968
Source: PubMed


The mechanisms that determine whether a tumor cell that has disseminated to a secondary site will resume growth immediately, die or enter a state of dormancy are poorly understood. Although tumor dormancy represents a common clinical finding, studying the mechanisms behind this stage of tumor progression has been challenging. Furthermore, it is thought that dormant tumor cells are refractory to chemotherapy due to their lack of proliferation. However, whether this is the only reason for their chemo-resistance remains to be proven. In this review we summarize recent findings that provide a mechanistic explanation about how stress signaling through the p38(SAPK) pathway and ER-stress signaling may coordinate the induction of growth arrest and drug-resistance in a model of squamous carcinoma dormancy. We further discuss how dormant tumor cells may enter this stage to adapt to strenuous conditions that do not favor immediate growth after dissemination. Finally, we propose that this response may recapitulate an evolutionarily conserved program of life-span extension through adaptation and tolerance to stress.

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    • "p38 is activated through phosphorylation at the Thr180-Gly-Tyr182 motif by MKK3, MKK4, and MKK6 [13]. Phosphorylated p38 activates a wide range of substrates that include transcription factors, protein kinases, and nuclear proteins, leading to diverse responses such as inflammatory responses, cell differentiation, cell-cycle arrest, apoptosis, senescence, cytokine production, and regulation of RNA splicing [14], [15]. The specific inhibitors, inactivating p38 by directly or indirectly acting on ATP-binding pocket [16], have been reported that could enhance the treatment effect of all-trans-retinoic acid in acute promyelocytic leukemia cell [17], arsenic trioxide in chronic myeloid leukemia cell [18] and bortezomib in multiple myeloma cell [19]. "
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    ABSTRACT: ATP-binding-cassette family membrane proteins play an important role in multidrug resistance. In this study, we investigated BIRB796, an orally active inhibitor of p38 mitogen-activated protein kinase, reversed MDR induced by ABCB1, ABCG2 and ABCC1. Our results showed that BIRB796 could reverse ABCB1-mediated MDR in both the drug selected and transfected ABCB1-overexpressing cell models, but did not enhance the efficacy of substrate-chemotherapeutical agents in ABCC1 or ABCG2 overexpression cells and their parental sensitive cells. Furthermore, BIRB796 increased the intracellular accumulation of the ABCB1 substrates, such as rhodamine 123 and doxorubicin. Moreover, BIRB796 bidirectionally mediated the ATPase activity of ABCB1, stimulating at low concentration, inhibiting at high concentration. However, BIRB796 did not alter the expression of ABCB1 both at protein and mRNA level. The down-regulation of p38 by siRNA neither affected the expression of ABCB1 nor the cytotoxic effect of paclitaxel on KBV200. The binding model of BIRB796 within the large cavity of the transmembrane region of ABCB1 may form the basis for future lead optimization studies. Importantly, BIRB796 also enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBV200 cell xenografts in nude mice. Overall, we conclude that BIRB796 reverses ABCB1-mediated MDR by directly inhibiting its transport function. These findings may be useful for cancer combinational therapy with BIRB796 in the clinic.
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    • "Alleviation of ER stress is achieved by the unfolded protein response (UPR). One arm of the UPR induces the activities of transcriptional factors, such as Xbp1, allowing survival signaling without affecting proliferation (Carrasco et al., 2007; Koong et al., 2006; Ranganathan et al., 2006a; Romero-Ramirez et al., 2004). The other arm consists in the attenuation of protein synthesis via Ser 52 phosphorylation of the ␣ subunit of the translation initiation factor eIF2 (Kaufman, 2002), thus preventing cyclin D1 expression and inducing arrest in G0/G1 (Brewer et al., 1999). "
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    ABSTRACT: Dihydroceramides, the precursors of ceramides in the de novo sphingolipid synthesis, have been recently implicated in active signalling. We previously demonstrated that dihydroceramide accumulation, in response to treatment with the dihydroceramide desaturase inhibitor XM462, induced autophagy with no sign of cell death in the gastric carcinoma HCG27 cell line. Here we show that XM462 treatment induces a transient early increase in dihydroceramides that are successively metabolized into other sphingolipids. Dihydroceramides accumulation is associated with cyclin D1 expression modulation, delayed G1/S transition of cell cycle and increased autophagy. Moreover, XM462 treatment induces ER stress via the activation of the translation inhibitor eIF2α and the pro-survival transcriptional factor Xbp1. Exogenous addition of a short chain dihydroceramide analog reproduces the effects of endogenous accumulation of dihydroceramides, causing cell cycle delay of the G1/S transition, autophagy enhancement, eIF2α activation and Xbp1 splicing. Blocking autophagy with 3-methyladenine abrogates the effect of XM462 on cell cycle and reduces cell survival to XM462 treatment. Furthermore, the XM462-induced survival response is able to reduce etoposide toxicity in HCG27 and HCT116 cancer cells. Our data suggest a role of dihydroceramide in regulating cell proliferation and survival.
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    • "These steps are usually followed by extravasation into the surrounding tissue, survival in the foreign microenvironment, proliferation, and induction of angiogenesis (Figure 1). It has become apparent that the vast majority of tumor cells within the primary tumor and also the disseminated tumor cells will not form distant metastases , either because they die or remain dormant [4]. The dormancy phenomenon probably explains what is seen in the clinic in which some cancer patients remain free of clinical evidence of metastatic disease for years or even decades after primary tumor resection, and after this prolonged period of time these patients show signs of tumor relapse. "
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