Cardiac phosphoproteome reveals cell signaling events involved in doxorubicin cardiotoxicity

Gratia, Séverine; Kay, Laurence; Michelland, Sylvie; Sève, Michel; Schlattner, Uwe; Tokarska‐Schlattner, Malgorzata

doi:10.1016/j.jprot.2012.02.004

Cited by 23 publications

(18 citation statements)

References 65 publications

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“…Thereby, ANTs are retained at high concentrations in the mitochondrial compartment, particularly in the proximity of cardiolipin-associated proteins, such as the NADH dehydrogenase-complex I. Mitochondria have been repeatedly suggested as the most important target for ANT cardiotoxicity (18,43,175,271,285), and similar results have been also suggested by recent unbiased proteomic and phosphoproteomic investigations ( Fig. 5) (79,254). ANTs have been reported to directly and indirectly interact with mitochondrial oxidative phosphorylation.…”

supporting

confidence: 61%

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

Štěrba

Popelová

Vávrová

et al. 2013

Antioxidants & Redox Signaling

269

192

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supporting

confidence: 61%

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

Štěrba

Popelová

Vávrová

et al. 2013

Antioxidants & Redox Signaling

269

192

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“…A study on the cardiac phosphoproteome has already shown PHB1 to be a prime target of doxorubicin [ 20 ]. Nonetheless, how the PHB proteins participate in the survival mechanisms against doxorubicin-mediated cardiotoxicity was not known.…”

Section: Discussionmentioning

confidence: 99%

FL3, a Synthetic Flavagline and Ligand of Prohibitins, Protects Cardiomyocytes via STAT3 from Doxorubicin Toxicity

et al. 2015

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AimsThe clinical use of doxorubicin for the treatment of cancer is limited by its cardiotoxicity. Flavaglines are natural products that have both potent anticancer and cardioprotective properties. A synthetic analog of flavaglines, FL3, efficiently protects mice from the cardiotoxicity of doxorubicin. The mechanism underlying this cardioprotective effect has yet to be elucidated.Methods and ResultsHere, we show that FL3 binds to the scaffold proteins prohibitins (PHBs) and thus promotes their translocation to mitochondria in the H9c2 cardiomyocytes. FL3 induces heterodimerization of PHB1 with STAT3, thereby ensuring cardioprotection from doxorubicin toxicity. This interaction is associated with phosphorylation of STAT3. A JAK2 inhibitor, WP1066, suppresses both the phosphorylation of STAT3 and the protective effect of FL3 in cardiomyocytes. The involvement of PHBs in the FL3-mediated cardioprotection was confirmed by means of small interfering RNAs (siRNAs) targeting PHB1 and PHB2. The siRNA knockdown of PHBs inhibits both phosphorylation of STAT3 and the cardioprotective effect of FL3.ConclusionActivation of mitochondrial STAT3/PHB1 complex by PHB ligands may be a new strategy against doxorubicin-induced cardiotoxicity and possibly other cardiac problems.

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“…We and others have shown that IL-6 increases expression of PHB through Stat3 transcriptional activation to promote survival of IECs, cardiomyocytes, and hepatocytes [53-55, 57]. IL-6 protective effects in cardiomyocytes are dependent upon IL-6 induction of PHB [58] and phosphorylation of mitochondrial S727-Stat3 [59]. Future studies will assess whether IL-6 mediates protection against mitochondrial dysfunction in IECs through modulation of PHB levels and phosphorylation of Stat3 at S727.…”

Section: Discussionmentioning

confidence: 99%

Prohibitin 1 modulates mitochondrial function of Stat3

Han

Souza

et al. 2014

Cellular Signalling

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Mitochondrial dysfunction in intestinal epithelial cells (IEC) is thought to precede the onset of inflammatory bowel diseases (IBD). Expression of Prohibitin 1 (PHB), a mitochondrial protein required for optimal electron transport chain (ETC) activity, is decreased in mucosal biopsies during active and inactive IBD. In addition to its activities as a transcription factor, Signal Transducer and Activator of Transcription 3 (Stat3) resides in the mitochondria of cells where phosphorylation at S727 is required for optimal ETC activity and protects against stress-induced mitochondrial dysfunction. Here, we show that PHB overexpression protects against mitochondrial stress and apoptosis of cultured IECs induced by TNFα, which is a pro-inflammatory cytokine involved in IBD pathogenesis. Expression of pS727-Stat3 dominant negative eliminates protection by PHB against TNFα-induced mitochondrial stress and apoptosis. PHB interacts with pS727-Stat3 in the mitochondria of cultured IECs and in colonic epithelium from wild-type mice. Our data suggest a protective role of PHB that is dependent on pS727-Stat3 to prevent mitochondrial dysfunction in IECs. Reduced levels of PHB during IBD may be an underlying factor promoting mitochondrial dysfunction of the intestinal epithelium.

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Cardiac phosphoproteome reveals cell signaling events involved in doxorubicin cardiotoxicity

Cited by 23 publications

References 65 publications

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

FL3, a Synthetic Flavagline and Ligand of Prohibitins, Protects Cardiomyocytes via STAT3 from Doxorubicin Toxicity

Prohibitin 1 modulates mitochondrial function of Stat3

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