AICAR stimulates IL-6 production via p38 MAPK in cardiac fibroblasts in adult mice: A possible role for AMPK

Du, Jianhai; Xu, Ning; Song, Yao; Xu, Ming; Lu, Zengjun; Han, Chide; Zhang, Youyi

doi:10.1016/j.bbrc.2005.09.174

Cited by 52 publications

(53 citation statements)

References 48 publications

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“…As indicated previously, p38 MAPK and JNK activation lead to mitochondrial apoptotic pathway (36,37), and JNK activation promotes processing of Bid to proapoptotic cleavage product (38). To date, several studies using pharmacologic or molecular approaches have indicated that AMPK was an upstream regulating molecule for activation of p38 (37,39,40), JNK (14,41), and ERK (42). Our results using selective inhibitors indicated that JNK and p38 contribute to AICAR sensitization of TRAIL-and TNFa-induced apoptosis, and their activities were actually enhanced by the presence of AICAR together with TRAIL and TNFa.…”

Section: Discussionmentioning

confidence: 77%

5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNFα-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling

Chao

Chen

et al. 2007

Molecular Cancer Therapeutics

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Death receptor-mediated tumor cell death, either alone or in combination with other anticancer drugs, is considered as a new strategy for anticancer therapy. In this study, we have investigated the effects and molecular mechanisms of 5-aminoimidazole-4-carboxamide riboside [AICAR; a pharmacologic activator of AMP-activated protein kinase (AMPK)] in sensitizing tumor necrosis factor (TNF) -related apoptosis-inducing ligand (TRAIL) -and TNFA-induced apoptosis of human colon cancer HCT116 cells. The cytotoxic action of AICAR requires AMPK activation and may occur at various stages of apoptotic pathways. AICAR cotreatment with either TRAIL or TNFA enhances activities of caspase-8, caspase-9, and caspase-3; down-regulates the antiapoptotic protein Bcl-2; increases the cleavage of Bid and results in the decrease of mitochondrial membrane potential; potentiates activation of p38 and c-Jun NH 2 -terminal kinase; and inhibits nuclear factor-KB activity. In addition, this sensitized cell apoptosis was neither observed in p53-null HCT116 cells nor affected by the cotreatment with mevalonate. In summary, we have developed a novel strategy of combining AICAR with TRAIL for the treatment of colon cancer cells. The sensitization effect of AICAR in cell apoptosis was mediated through AMPK pathway, requires p53 activity, and involves mitochondria-dependent apoptotic cascades, p38 and c-Jun NH 2 -terminal kinase. [Mol Cancer Ther 2007;6(5):1562 -71]

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Section: Discussionmentioning

confidence: 77%

5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNFα-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling

Chao

Chen

et al. 2007

Molecular Cancer Therapeutics

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“…Studies in rat neonatal cardiomyocytes have shown that multiple stimuli that activate AMPK (simulated ischemia, AICAR, metformin) also increase p38 MAPK phosphorylation. Although it was concluded that p38 MAPK is downstream of AMPK, it was not determined if AMPK inhibition blocked p38 MAPK phosphorylation (32). Perhaps the most convincing evidence for AMPK mediation of p38 MAPK signaling in the heart comes from a study where AICAR increased p38 phosphorylation, and hearts deficient in AMPKα2 activity had significantly reduced p38 MAPK activation in response to low-flow ischemia (30).…”

Section: Discussionmentioning

confidence: 99%

Dissociation of AMP-activated protein kinase and p38 mitogen-activated protein kinase signaling in skeletal muscle

Fujii

Witters

et al. 2007

Biochemical and Biophysical Research Communications

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AMP-activated protein kinase (AMPK) is widely recognized as an important regulator of glucose transport in skeletal muscle. The p38 mitogen-activated protein kinase (MAPK) has been proposed to be a component of AMPK-mediated signaling. Here we used several different models of altered AMPK activity to determine whether p38 MAPK is a downstream intermediate of AMPK-mediated signaling in skeletal muscle. First, L6 myoblasts and myotubes were treated with AICAR, an AMPK stimulator. AMPK phosphorylation was significantly increased, but there was no change in p38 MAPK phosphorylation. Similarly, AICAR incubation of isolated rat extensor digitorum longus (EDL) muscles did not increase p38 phosphorylation. Next, we used transgenic mice expressing an inactive form of the AMPKα2 catalytic subunit in skeletal muscle (AMPKα2i TG mice). AMPKα2i TG mice did not exhibit any defect in basal or contraction-induced p38 MAPK phosphorylation. We also used transgenic mice expressing an activating mutation in the AMPKγ1 subunit (γ1R70Q TG mice). Despite activated AMPK, basal p38 MAPK phosphorylation was not different between wild type and γ1R70Q TG mice. In addition, muscle contraction-induced p38 MAPK phosphorylation was significantly blunted in the γ1R70Q TG mice. In conclusion, increasing AMPK activity by AICAR and AMPKγ1 mutation does not increase p38 MAPK phosphorylation in skeletal muscle. Furthermore, AMPKα2i TG mice lacking contraction-stimulated AMPK activity have normal p38 MAPK phosphorylation. These results suggest that p38 MAPK is not a downstream component of AMPK-mediated signaling in skeletal muscle.

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“…Metformin, the most commonly used drug for the treatment of type II diabetes, has been shown to improve cardiovascular function and reduce cardiovascular risks in diabetic patients through the activation of AMPK (reviewed in refs. [39][40][41][42]. Phenformin and AICAR have also demonstrated the ability to activate AMPK and exert cardioprotective functions.…”

Section: Ampk Activation and Cardiac Protectionmentioning

confidence: 99%

“…Phenformin and AICAR have also demonstrated the ability to activate AMPK and exert cardioprotective functions. 37,39,41,43 Not only can the activation of AMPK protect the heart, but the activation of AMPK and the induction of catabolism in the tumor cells may pose a logical strategy for combinational therapy. The high glycolytic rate and increased glucose uptake of tumors were first reported by Warburg.…”

Section: Ampk Activation and Cardiac Protectionmentioning

confidence: 99%

Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells

Shell¹,

Lyass²,

Trusk³

et al. 2008

Cell Cycle

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ErbB2 targeted therapies represent an attractive strategy in breast cancer. Herceptin, an anti-ErbB2 monoclonal antibody, is an approved treatment for patients with ErbB2-overexpressing breast cancers. ErbB2 signaling can also be blocked using small molecule tyrosine kinase inhibitors, like Lapatinib, that compete with ATP for binding at the ErbB2 catalytic kinase domain. The principal adverse event attributable to Herceptin is cardiac toxicity. Data from clinical trials show that, unlike Herceptin, Lapatinib may have reduced cardiac toxicity. This study was conducted to elucidate pathways which may contribute to cardiac toxicity or survival using Lapatinib and Herceptin. Our results show that treatments directed to ErbB1/2 receptors using GW-2974 (a generic ErbB1/2 inhibitor) activated AMPK, a key regulator in mitochondrial energy production pathways in human cardiac cells and cancer cells. Although Herceptin downregulates tumor survival pathways, AMPK fails to be activated in tumor and cardiac cells. When treated in combination with TNFα, a known cytokine associated with cardiac toxicity, GW-2974 protected cardiac cells from cell death whereas Herceptin contributed to TNFα-induced cellular killing. Since activity of AMPK in cardiac cells is associated with stress induced survival in response to cytokines or energy depletion, cardiac toxicity by Herceptin may be a consequence of failure to induce stress-related survival mechanisms. Thus, the ability to activate AMPK after treatment with tyrosine kinase inhibitors may be a crucial factor for increased efficacy against the tumor and decreased risk of cardiomyopathy.

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AICAR stimulates IL-6 production via p38 MAPK in cardiac fibroblasts in adult mice: A possible role for AMPK

Cited by 52 publications

References 48 publications

5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNFα-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling

5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNFα-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling

Dissociation of AMP-activated protein kinase and p38 mitogen-activated protein kinase signaling in skeletal muscle

Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells

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