Differential roles of p38-MAPK and JNKs in mediating early protection or apoptosis in the hyperthermic perfused amphibian heart

Gaitanaki, Catherine; Mastri, Michalis; Aggeli, Ioanna-Katerina; Beis, Isidoros

doi:10.1242/jeb.018960

Cited by 30 publications

(28 citation statements)

References 56 publications

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“…These results indicated that the MAPK pathway was potentially involved in transducing the signals from extracellular stimuli to the nucleus for transcriptional changes and consequent induction of apoptosis. JNK and p38-MAPK are well-known stress-activated protein kinases that evoke sequential interactions related to cell death or survival [50]. In particular, p38 is also a marker of oxidative stress, which increases the phosphorylation levels of p38 [44, 51], consistent with our findings and supporting the claim that oxidative stress is involved in the mechanism underlying the combined treatment.…”

Section: Discussionsupporting

confidence: 90%

Baicalin Augments Hyperthermia-Induced Apoptosis in U937 Cells and Modulates the MAPK Pathway via ROS Generation

Zakki

Cui

Sun

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hyperthermia is a widely used therapeutic tool for cancer therapy and a well-known inducer of apoptosis. Although the flavonoid compound baicalin (BCN) is a potent anticancer agent for several human carcinomas, it is less potent in the human U937 myelomonocytic leukemia cell line. To explore any enhancing effects of BCN on hyperthermia-induced apoptosis, this study investigated the combined effects and apoptotic mechanisms of hyperthermia and BCN in U937 cells. Methods: U937 cells were heat treated at 44ºC for 12 min with or without pre-treatment with BCN (10-50 µM) and then incubated for 6 h at 37 ºC with 5% CO₂ and 95% air. Cell viability was analyzed by Trypan blue exclusion assay. Apoptosis was examined by DNA fragmentation, fluorescence microscopy and flow cytometry. Generation of mitochondrial trans-membrane potential (MMP), mitochondrial calcium, and reactive oxygen species (ROS) was also detected by flow cytometry. The expression of proteins related to apoptosis and signaling pathways was determined by western blotting. Results: Hyperthermia alone did not reduce cell viability or induce notable levels of apoptosis, but combined hyperthermia and BCN treatment markedly augmented apoptosis by upregulating proapoptotic proteins and suppressing antiapoptotic proteins, culminating in caspase-3 activation. Mitochondrial transmembrane potential was significantly decreased, and generation of reactive oxygen species (ROS) and suppression of antioxidant enzymes were marked. Furthermore, with the combined treatment, the phosphorylated forms of JNK and p38 showed increased expression, whereas AKT was dephosphorylated. JNK-IN-8 (a JNK inhibitor) and NAC (a ROS scavenger) abrogated the apoptotic effects of the combined treatment, significantly protecting the cells and indicating the involvement of high ROS generation and the MAPK pathway in the underlying molecular mechanism. Conclusion: This study provides compelling evidence that hyperthermia, in combination with BCN, is a promising therapeutic strategy for enhancement of apoptosis and suggest a promising therapeutic approach for cancer.

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Section: Discussionsupporting

confidence: 90%

Baicalin Augments Hyperthermia-Induced Apoptosis in U937 Cells and Modulates the MAPK Pathway via ROS Generation

Zakki

Cui

Sun

et al. 2018

Cell Physiol Biochem

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“…What is more, the observed sustained activation of p38-MAPK could underscore the critical role of this kinase under the interventions investigated. Such a hypothesis may be justified as activation of p38-MAPK has been shown to exert a beneficial role in various experimental models exposed to stressful conditions (Lavoie et al, 1995;Clerk et al, 1998) as well as in the isolated perfused amphibian heart subjected to hyperthermia (Gaitanaki et al, 2008). Nevertheless, no data are available so far regarding the potential effect of p38-MAPK on the modulation of gene expression in mussels.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, in an effort to evaluate the biological impact of hyperthermia in mussels and with heat stress known to favour apoptosis (Gaitanaki et al, 2008;Bellmann et al, 2009), we assessed the occurrence of apoptosis. Detection of cleaved fragments of PARP by immunoblotting 8h after the onset of hyperthermia (Fig.2B) substantiated the delayed initiation of the apoptotic process, which also explains the high mortality rate for mussels observed after exposure to 30°C for 24h.…”

Section: Discussionmentioning

confidence: 99%

Hyperthermia-induced Hsp70 and MT20 transcriptional upregulation are mediated by p38-MAPK and JNKs inMytilus galloprovincialis(Lamarck); a pro-survival response

Gourgou

Aggeli

Beis

et al. 2010

Journal of Experimental Biology

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SUMMARYIn the present study we investigated the signal transduction cascades triggered by acute thermal stress in Mytilus galloprovincialis gills. This particular species has been reported to exhibit a significant tolerance to high temperatures; thus, it was intriguing to examine the molecular mechanisms responsible for this extraordinary trait. In particular, exposure to 30°C was found to cause a significant and sustained stimulation of p38-MAPK phosphorylation while the activation profile of JNKs was transient and relatively moderate. We also observed that hyperthermia induced apoptosis as a delayed response, with both MAPK subfamilies rapidly translocating to the nucleus. The phosphorylation of cJun, ATF2 and NFB was detected next. Using selective inhibitors, phosphorylation of these transcription factors was established to be dependent on p38-MAPK or JNKs. Subsequently, potential changes in gene expression were assessed. In this context, hyperthermia resulted in the transcriptional upregulation of Hsp70 and MT20 genes with a widely known salutary effect, preserving mussel fitness and performance under adverse environmental conditions. Interestingly, p38-MAPK and JNKs were found to mediate the hyperthermia-induced Hsp70 and MT20 upregulation as well as the delayed induction of apoptosis under the interventions studied. Overall this is, to our knowledge, the first time that an insight into the compensatory survival 'programme' initiated in Mytilus galloprovincialis gills, contributing to this organism's exceptional tolerance to thermal stress, has been gained. In particular, we provide evidence demonstrating the principal role of p38-MAPK and JNKs in transducing the stress signal via mobilization of specific transcription factors and the transcriptional upregulation of cytoprotective genes.

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“…Exposure of M. galloprovincialis to 30°C was found to cause a significant and sustained stimulation of p38-MAPK phosphorylation while the activation profile of JNKs was transient and relatively moderate in gill tissue (Gourgou et al, 2010;Evans and Somero, 2010). It was demonstrated that p38-MAPK phosphorylation was activated more rapidly and strongly than that of JNKs in the isolated perfused heart of the frog Rana ridibunda at 42°C (Gaitanaki et al, 2008), further indicating that p38 and JNKs might play different roles in animals during temperature stress.…”

Section: Stress-signaling Proteinsmentioning

confidence: 94%

The impact of acute temperature stress on hemocytes of invasive and native mussels (Mytilus galloprovincialisandM. californianus): DNA damage, membrane integrity, apoptosis and signalling pathways

Yao

Somero

2012

Journal of Experimental Biology

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SUMMARYWe investigated the effects of acute heat stress and cold stress on cell viability, lysosome membrane stability, double-and singlestranded DNA breakage, and signaling mechanisms involved in cellular homeostasis and apoptosis in hemocytes of native and invasive mussels, Mytilus californianus and Mytilus galloprovincialis, respectively. Both heat stress (28, 32°C) and cold stress (2, 6°C) led to significant double-and single-stranded breaks in DNA. The type and extent of DNA damage were temperature and time dependent, as was caspase-3 activation, an indicator of apoptosis, which may occur in response to DNA damage. Hemocyte viability and lysosomal membrane stability decreased significantly under heat stress. Western blot analyses of hemocyte extracts with antibodies for proteins associated with cell signaling and stress responses [including members of the phospho-specific mitogen-activated protein kinase (MAPK) family c-JUN NH 2 -terminal kinase (JNK) and p38-MAPK, and apoptosis executor caspase-3] revealed that heat and cold stress induced a time-dependent activation of JNK, p38-MAPK and caspase-3 and that these signaling and stress responses differed between species. The thermal limits for activation of cell signaling processes linked to the repair of stress-induced damage may help determine cellular thermal tolerance limits. Our results show similarities in responses to cold and heat stress and suggest causal linkages between levels of DNA damage at both extremes of temperature and downstream regulatory responses, including induction of apoptosis. Compared with M. californianus, M. galloprovincialis might have a wider temperature tolerance due to a lower amount of single-and double-stranded DNA damage, faster signaling activation and transduction, and stronger repair ability against temperature stress.

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Differential roles of p38-MAPK and JNKs in mediating early protection or apoptosis in the hyperthermic perfused amphibian heart

Cited by 30 publications

References 56 publications

Baicalin Augments Hyperthermia-Induced Apoptosis in U937 Cells and Modulates the MAPK Pathway via ROS Generation

Baicalin Augments Hyperthermia-Induced Apoptosis in U937 Cells and Modulates the MAPK Pathway via ROS Generation

Hyperthermia-induced Hsp70 and MT20 transcriptional upregulation are mediated by p38-MAPK and JNKs inMytilus galloprovincialis(Lamarck); a pro-survival response

The impact of acute temperature stress on hemocytes of invasive and native mussels (Mytilus galloprovincialisandM. californianus): DNA damage, membrane integrity, apoptosis and signalling pathways

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