The Jun Kinase/Stress-activated Protein Kinase Pathway Functions to Regulate DNA Repair and Inhibition of the Pathway Sensitizes Tumor Cells to Cisplatin

Potapova, Olga; Haghighi, A. Pejmun; Bost, Fréd́eric; Liu, Chaoting; Birrer, Michael J.; Gjerset, Ruth A.; Mercola, Dan

doi:10.1074/jbc.272.22.14041

Cited by 216 publications

(208 citation statements)

References 28 publications

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“…Moreover, c-Jun )/) fibroblasts are relatively resistant to apoptosis induced by alkylating agents (23) and UV (24), and show impaired FasL expression. But in some other cases the conclusions are exactly opposite to these findings (25). These results imply that the c-Jun/AP-1 response depends on the type of cells and stresses.…”

Section: Primary Metastatic C-junmentioning

confidence: 58%

During Human Melanoma Progression AP‐1 Binding Pairs are Altered with Loss of c‐Jun In Vitro

Yang

McNulty

Meyskens

2004

Pigment Cell Research

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We demonstrated previously that c‐Jun, JunB and c‐Fos RNA were dysregulated in metastatic melanoma cells compared with normal human melanocytes. The purpose of this study was to evaluate the distribution in composition of AP‐1 dimers in human melanoma pathogenesis. We investigated AP‐1 dimer pairing in radial growth phase‐like (RGP) (w3211) and vertical growth phase‐like (VGP) (w1205) human melanoma cells and metastatic cell lines (cloned from patients, c83‐2c, c81‐46A, A375, respectively) compared with melanocytes using electrophoretic mobility shift assay (EMSA), Western blot and transfection analyses. There are progressive variations in AP‐1 composition in different melanoma cell lines compared with normal melanocytes, in which c‐Jun, JunD and FosB were involved in AP‐1 complexes. In w3211, c‐Jun, JunD and Fra‐1 were involved in AP‐1 binding, while in w1205, overall AP‐1 binding activity was decreased significantly and supershift binding was detected only with JunD antibodies. In metastatic c81‐46A and A375 cells, only JunD was involved in AP‐1 binding activity, but in a third (c83‐2c) c‐Jun, JunD and Fra‐1 were present. Western blot evaluation detected c‐Jun in melanocytes and w3211, but this component was decreased significantly or was not detectable in w1205, c81‐46A and A375 cells. In contrast, JunD protein was elevated in c81‐46A and c83‐2c cells compared with melanocytes and RGP and VGP cell lines. Normal melanocytes and c83‐2c cells (which have c‐Jun involved in AP‐1 binding), transfected with c‐Jun antisense and treated with cisplatin, showed higher viability compared with untransfected cells, while in c81‐46A cells (in which only JunD is detectable) no change in cell viability was observed following treatment with cisplatin and c‐jun antisense transfection. A dominant‐negative c‐Jun mutant (TAM67) significantly increased the soft agar colony formation of w3211 and c83‐2c cells. These results suggest that components of AP‐1, especially c‐Jun, may offer a new target for the prevention or treatment of human melanoma progression.

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Section: Primary Metastatic C-junmentioning

confidence: 58%

During Human Melanoma Progression AP‐1 Binding Pairs are Altered with Loss of c‐Jun In Vitro

Yang

McNulty

Meyskens

2004

Pigment Cell Research

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“…However, other studies have also suggested that JNK/SAP kinase signaling may also play a cyto-protective role versus other toxic stresses, such as to the DNA damaging drug cisplatin (Potapova et al, 1997). Irradiation of A431 cells with either 1 Gy or 6 Gy caused similar activations of JNK1 (Figures 1 and 2), which lead to functional activation of c-Jun (Figure 3).…”

Section: Discussionmentioning

confidence: 83%

Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells

et al. 1998

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The molecular mechanism(s) by which tumor cells survive after exposure to ionizing radiation are not fully understood. Exposure of A431 cells to low doses of radiation (1 Gy) caused prolonged activations of the mitogen activated protein (MAP) kinase and stress activated protein (SAP) kinase pathways, and induced p21 Cip-1/WAF1 via a MAP kinase dependent mechanism. In contrast, higher doses of radiation (6 Gy) caused a much weaker activation of the MAP kinase cascade, but a similar degree of SAP kinase cascade activation. In the presence of MAP kinase blockade by the speci®c MEK1 inhibitor (PD98059) the basal activity of the SAP kinase pathway was enhanced twofold, and the ability of a 1 Gy radiation exposure to activate the SAP kinase pathway was increased *sixfold 60 min after irradiation. In the presence of MAP kinase blockade by PD98059 the ability of a single 1 Gy exposure to cause double stranded DNA breaks (TUNEL assay) was enhanced at least threefold over the following 24 ± 48 h. The increase in DNA damage within 48 h was also mirrored by a similar decrease in A431 cell growth as judged by MTT assays over the next 4 ± 8 days following radiation exposure. This report demonstrates that the MAP kinase cascade is a key cytoprotective pathway in A431 human squamous carcinoma cells which is activated in response to clinically used doses of ionizng radiation. Inhibition of this pathway potentiates the ability of low dose radiation exposure to induce cell death in vitro.

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“…By contrast, the expression of dnJUN resulted in enhanced sensitivity to a panel of DNA-damaging agents with different mechanisms of action, including UV-C, doxorubicin, daunorubicin, methionine-S-methyl sulfonium chloride (MMS), actinomycin D and etoposide. 39 Moreover, ATF2 may regulate cJUN transcript expression and often ATF2 inhibitors act interfering with the formation of cJUN/ATF2 heterodimers. 34,40 We observed an increased cJUN expression in response to incubation of cell lines with CDDP at both transcriptional and protein level.…”

Section: Discussionmentioning

confidence: 99%

ATF2 contributes to cisplatin resistance in non‐small cell lung cancer and celastrol induces cisplatin resensitization through inhibition of JNK/ATF2 pathway

Iacono

Monica

Vavalà

et al. 2014

Intl Journal of Cancer

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ATF2 is a transcription factor involved in stress and DNA damage. A correlation between ATF2 JNK-mediated activation and resistance to damaging agents has already been reported. The purpose of the present study was to investigate whether ATF2 may have a role in acquired resistance to cisplatin in non-small cell lung cancer (NSCLC). mRNA and protein analysis on matched cancer and corresponding normal tissues from surgically resected NSCLC have been performed. Furthermore, in NSCLC cell lines, ATF2 expression levels were evaluated and correlated to platinum (CDDP) resistance. Celastrol-mediated ATF2/cJUN activity was measured. High expression levels of both ATF2 transcript and proteins were observed in lung cancer specimens (p << 0.01, Log 2 (FC) 5 14.7). CDDP-resistant NSCLC cell lines expressed high levels of ATF2 protein. By contrast, Celastrol-mediated ATF2/cJUN functional inhibition restored the response to CDDP. Moreover, ATF2 protein activation correlates with worse outcome in advanced CDDP-treated patients. For the first time, it has been shown NSCLC ATF2 upregulation at both mRNA/protein levels in NSCLC. In addition, we reported that in NSCLC cell lines a correlation between ATF2 protein expression and CDDP resistance occurs. Altogether, our results indicate a potential increase in CDDP sensitivity, on Celastrolmediated ATF2/cJUN inhibition. These data suggest a possible involvement of ATF2 in NSCLC CDDP-resistance.Non-small cell lung cancer (NSCLC) is characterized by high incidence and mortality rate worldwide, being the most common subtypes represented by adenocarcinoma and squamous cell carcinoma. 1 Platinum-based chemotherapy in combination with other cytotoxic agents such as Gemcitabine, taxanes and vinorelbine represented the standard of care for unselected patients with advanced NSCLC. Recently, in nonsquamous histology, the combination of cisplatin (CDDP) and pemetrexed showed superior activity. 2,3 However, in chemotherapy-treated NSCLC, the duration of response is relatively short due to primary or acquired resistance to chemotherapy. 4 Patients with advanced disease may not derive any benefit from first-line chemotherapy, while they face significant treatment-related side effects. Consequently, it appears a logical approach to investigate alternative ways to increase the effectiveness outcomes of chemotherapy, through the identification of molecular features suggestive of a better therapeutic ratio.Activating transcription factor 2 (ATF2) is a member of the basic helix-loop-helix (b-ZIP) transcription factor family, whose transcriptional activities are mediated by stressactivated kinases JNK/p38 and activated by phosphorylation on threonine residues. 5,6 Independent of its transcriptional activity, ATF2 also plays an important role in the DNA damage response and in the regulation of intra-S-phase checkpoint (reviewed in Ref. 7). Several studies reported a correlation between ATF2/JNK-mediated activation and resistance to DNA damaging agents. Hayakawa et al. showed that stable expression of ATF...

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The Jun Kinase/Stress-activated Protein Kinase Pathway Functions to Regulate DNA Repair and Inhibition of the Pathway Sensitizes Tumor Cells to Cisplatin

Cited by 216 publications

References 28 publications

During Human Melanoma Progression AP‐1 Binding Pairs are Altered with Loss of c‐Jun In Vitro

During Human Melanoma Progression AP‐1 Binding Pairs are Altered with Loss of c‐Jun In Vitro

Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells

ATF2 contributes to cisplatin resistance in non‐small cell lung cancer and celastrol induces cisplatin resensitization through inhibition of JNK/ATF2 pathway

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