Oncogenic c-Myc and prothymosin-alpha protect hepatocellular carcinoma cells against sorafenib-induced apoptosis

Lin, Yi-Te; Lu, Hsing-Pang; Chao, Chuck C.‐K.

doi:10.1016/j.bcp.2014.10.012

Cited by 20 publications

(26 citation statements)

References 51 publications

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“…Prothymosin alpha (ProTα), a nuclear protein, is implicated in multiple functions including cell survival, proliferation and immunogenicity (Jiang et al, 2003;Mosoian, 2011;Ueda et al, 2012;Cannavo et al, 2013;Emmanouilidou et al, 2013;Ioannou et al, 2013;Chang et al, 2014;Lin et al, 2015). We previously identified ProTα as an anti-necrotic factor in the conditioned medium of a serum-free primary culture of cortical neurons (Ueda et al, 2007;Ueda, 2009).…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective impact of prothymosin alpha-derived hexapeptide against retinal ischemia–reperfusion

et al. 2016

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Prothymosin alpha (ProTα) has robustness roles against brain and retinal ischemia or serum-starvation stress. In the ProTα sequence, the active core 30-amino acid peptide/P30 (a.a.49-78) is necessary for the original neuroprotective actions against ischemia. Moreover, the 9-amino acid peptide sequence/P9 (a.a.52-60) in P30 still shows neuroprotective activity against brain and retinal ischemia, though P9 is less potent than P30. As the previous structure-activity relationship study for ProTα may not be enough, the possibility still exists that any sequence smaller than P9 retains potent neuroprotective activity. When different P9- and P30-related peptides were intravitreally injected 24h after retinal ischemia in mice, the 6-amino acid peptide/P6 (NEVDEE, a.a.51-56) showed potent protective effects against ischemia-induced retinal functional deficits, which are equipotent to the level of P30 peptide in electroretinography (ERG) and histological damage in Hematoxylin and Eosin (HE) staining. Further studies using ERG and HE staining suggested that intravitreal or intravenous (i.v.) injection with modified P6 peptide/P6Q (NEVDQE) potently inhibited retinal ischemia-induced functional and histological damage. In an immunohistochemical analysis, the ischemia-induced loss of retinal ganglion, bipolar, amacrine and photoreceptor cells were inhibited by a systemic administration with P6Q peptide 24h after the ischemic stress. In addition, systemic post-treatment with P6Q peptide significantly inhibited retinal ischemia-induced microglia and astrocyte activation in terms of increased ionized calcium-binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) intensity, respectively, as well as their morphological changes, increased number and migration. Thus, this study demonstrates the therapeutic significance of modified P6 peptide P6Q (NEVDQE) derived from 6-amino acid peptide (P6) in ProTα against ischemic damage.

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Section: Introductionmentioning

confidence: 99%

Neuroprotective impact of prothymosin alpha-derived hexapeptide against retinal ischemia–reperfusion

et al. 2016

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“…Apaf-1 and blocking apoptosome formation, suggesting that PTMA may represent a potential target for cancer therapy [23,31] . In our study, we found that PTMA inhibits Bax expression and translocation to mitochondria, pBad dephosphorylation, and cytochrome c release into the cytosol, therefore inhibiting the mitochondrial-dependent apoptosis pathway in sorafenib-treated HCC cells [32] .…”

Section: Ptma Prevents Apoptosis In Cancer Cells By Interacting Withmentioning

confidence: 53%

“…c-Myc binds to the proximal promoter and the first intron of the PTMA gene to upregulate PTMA transcription; on the other hand, one study showed that c-Myc did not regulate PTMA transcription [33][34][35][36] . In our study, we found that c-Myc/Max interacts with both the proximal promoter and first intron of the PTMA gene in HCC cells, but only the proximal promoter could be regulated through ERK kinase and sorafenib [32] . The different results reported in these studies suggest that the effects of PTMA may be dependent on cell type.…”

Section: Ptma Prevents Apoptosis In Cancer Cells By Interacting Withmentioning

confidence: 63%

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Sorafenib Induces Apoptosis in Hepatocellular Carcinoma Cells by Inhibiting c-Myc and Prothymosin-Alpha

Lin

Chao

2015

Can Cell Microenviron

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The anti-apoptotic protein prothymosin alpha (PTMA) is overexpressed in various cancers, including hepatocellular carcinoma (HCC). Earlier studies have shown that PTMA blocks apoptosis in cancer cells by inhibiting caspase-9 activation and apoptosome formation. Our recent study shows that silencing of PTMA potentiates the mitochondria-dependent apoptosis pathway in sorafenib-treated HCC cells, leading to Bax translocation, pBad dephosphorylation, and cytochrome c release. Our findings also indicate that the pERK/c-Myc/Max/PTMA axis represents a newly identified target of sorafenib in chemotherapy against HCC.

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“…Despite some progress, the overall efficacy of Sorafenib on advanced HCC remains moderate [5–9]. Several reasons for its lack of efficacy have been investigated, such as the escape from apoptosis, and formation of compensatory signaling pathways [10–12]. However, the reasons and mechanisms are still far from being understood.…”

Section: Introductionmentioning

confidence: 99%

Des-gamma-carboxy prothrombin antagonizes the effects of Sorafenib on human hepatocellular carcinoma through activation of the Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways

et al. 2016

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Despite significant progress, advanced hepatocellular carcinoma (HCC) remains an incurable disease, and the overall efficacy of targeted therapy by Sorafenib remains moderate. We hypothesized that DCP (des-gamma-carboxy prothrombin), a prothrombin precursor produced in HCC, might be one of the reasons linked to the low efficacy of Sorafenib. We evaluated the efficacy of Sorafenib in HLE and SK-Hep cells, both of which are known DCP-negative HCC cell lines. In the absence of DCP, Sorafenib effectively inhibited the growth of HCC and induced cancer cell apoptosis. In the presence of DCP, HCC was resistant to Sorafenib-induced inhibition and apoptosis, as determined by in vitro assays and in mice xenografted with HLE cells. Molecular analysis of HLE xenografted-nude mice showed that DCP activates the transduction of the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR cascades. DCP might stimulate the formation of compensatory feedback loops in the intricately connected signaling pathways when kinases are targeted by Sorafenib. Our results indicate that DCP antagonizes the inhibitory effects of Sorafenib on HCC through activation of the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR signaling pathways. Taken together, our findings define a DCP-mediated mechanism of inhibition of Sorafenib in HCC, which is critical for targeting therapy in advanced HCC.

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Oncogenic c-Myc and prothymosin-alpha protect hepatocellular carcinoma cells against sorafenib-induced apoptosis

Cited by 20 publications

References 51 publications

Neuroprotective impact of prothymosin alpha-derived hexapeptide against retinal ischemia–reperfusion

Neuroprotective impact of prothymosin alpha-derived hexapeptide against retinal ischemia–reperfusion

Sorafenib Induces Apoptosis in Hepatocellular Carcinoma Cells by Inhibiting c-Myc and Prothymosin-Alpha

Des-gamma-carboxy prothrombin antagonizes the effects of Sorafenib on human hepatocellular carcinoma through activation of the Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways

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