A novel non-phosphorylated potential antitumoral peptide inhibits STAT3 biological activity☆

Dourlat, Jennifer; Liu, Wang‐Qing; Sancier, Florence; Edmonds, Thomas; Pamonsinlapatham, Perayot; Cruzalegui, Francisco; Garbay, Christiane

doi:10.1016/j.biochi.2009.05.006

Cited by 10 publications

(6 citation statements)

References 42 publications

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“…Kinase inhibitors that interfere with the activation step, e.g., the Jak-kinase inhibitor AG490, Jak-Inhibitor I, and WP1066, or compounds, which affect multiple other targets in addition to STAT3, e.g., curcumin, resveratrol, and platinum compounds, have been investigated. Several other compounds might be rather STAT3 specific, among them are hpSt3dODN, Stattic, S3I-M2001, cucurbitacin, peptide P1a, and our previously identified peptide aptamer hTrx-3.8 that targets the STAT3-SH2 domain (23,(39)(40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death

Borghouts

Tittmann

Delis

et al. 2010

Molecular Cancer Research

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Signaling components, which confer an "addiction" phenotype on cancer cells, represent promising drug targets. The transcription factor signal transducers and activators of transcription 3 (STAT3) is constitutively activated in many different types of tumor cells and its activity is indispensible in a large fraction. We found that the expression of the endogenous inhibitor of STAT3, protein inhibitor of activated STAT3 (PIAS3), positively correlates with STAT3 activation in normal cells. This suggests that PIAS3 controls the extent and the duration of STAT3 activity in normal cells and thus prevents its oncogenic function. In cancer cells, however, the expression of PIAS3 is posttranscriptionally suppressed, possibly enhancing the oncogenic effects of activated STAT3. We delimited the interacting domains of STAT3 and PIAS3 and identified a short fragment of the COOH-terminal acidic region of PIAS3, which binds strongly to the coiled-coil domain of STAT3. This PIAS3 fragment was used to derive the recombinant STAT3-specific inhibitor rPP-C8. The addition of a protein transduction domain allowed the efficient internalization of rPP-C8 into cancer cells. This resulted in the suppression of STAT3 target gene expression, in the inhibition of migration and proliferation, and in the induction of apoptosis at low concentrations [half maximal effective concentration (EC 50 ), <3 μmol/L]. rPP-C8 did not affect normal fibroblasts and represents an interesting lead for the development of novel cancer drugs targeting the coiled-coil domain of STAT3. Mol Cancer Res; 8(4); 539-53. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death

Borghouts

Tittmann

Delis

et al. 2010

Molecular Cancer Research

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“…reported a similar phenomenon with the STAT3-binding sequence, AYRNRpYRRQYRY, wherein the corresponding non-phosphorylated sequence was found to be equipotent and effectively retained Stat3 inhibitory activity. 26 Poor cell permeability and dephosphorylation by intracellular and/or cell surface phosphatases/esterasase of phosphate ester containing inhibitors have led to the development of a number of successful protecting group/prodrug strategies, including difluorophosphonates and POM protecting group strategies. 27 However, phosphate group modulation was beyond the scope of this study.…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis, and in vitro characterization of novel hybrid peptidomimetic inhibitors of STAT3 protein

Shahani

Yue

Fletcher

et al. 2011

Bioorganic & Medicinal Chemistry

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Aberrant activation of oncogenic signal transducer and activator of transcription 3 (STAT3) protein signaling pathways has been extensively implicated in human cancers. Given STAT3’s prominent dysregulatory role in malignant transformation and tumorigenesis, there has been a significant effort to discover STAT3-specific inhibitors as chemical probes for defining the aberrant STAT3-mediated molecular events that support the malignant phenotype. To identify novel, STAT3-selective inhibitors suitable for interrogating STAT3 signaling in tumor cells, we explored the design of hybrid molecules by conjugating a known STAT3 inhibitory peptidomimetic, ISS610 to the high-affinity STAT3-binding peptide motif derived from the ILR/gp-130. Several hybrid molecules were examined in in vitro biophysical and biochemical studies for inhibitory potency against STAT3. Lead inhibitor 14aa was shown to strongly bind to STAT3 (KD = 900 nM), disrupt STAT3:phosphopeptide complexes (Ki = 5 μM) and suppress STAT3 activity in in vitro DNA-binding activity/ electrophoretic mobility shift assay (EMSA). Moreover, lead STAT3 inhibitor 14aa induced a time-dependent inhibition of constitutive STAT3 activation in v-Src transformed mouse fibroblasts (NIH3T3/v-Src), with 80 % suppression of constitutively-active STAT3 at six hours following treatment of NIH3T3/v-Src. However, STAT3 activity recovered at 24 hours after treatment of cells, suggesting potential degradation of the compound. Results further showed a suppression of aberrant STAT3 activity in NIH3T3/v-Src by the treatment with compound 14aa-OH, which is the non-pTyr version of compound 14aa. The effect of compounds 14aa and 14aa-OH are accompanied by a moderate loss of cell viability.

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“…We detected the presence of peptides AYRNRYRRQYRY, EQRPRT, and LPTSEAAKY in glutelin fraction, which might be responsible for the antiproliferative effect. Although we do not have experimental data, it is possible those last two peptides might play an important role in the inhibition of the transcription factor STAT3, which mediates the expression of various genes involved in cell proliferation and apoptosis [ 12 ]. In conclusion, we demonstrated that digested tryptic protein samples, which contain encrypted peptides, are able to exert an antiproliferative activity on neoplastic cells.…”

Section: Discussionmentioning

confidence: 99%

Characterization and Identification of Cryptic Biopeptides inCarya illinoinensis(Wangenh K. Koch) Storage Proteins

Mares-Mares

Gutiérrez-Vargas

Pérez-Moreno

et al. 2017

BioMed Research International

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The objective of this research was to identify and characterize the encoded peptides present in nut storage proteins of Carya illinoinensis. It was found, through in silico prediction, proteomic analysis, and MS spectrometry, that bioactive peptides were mainly found in albumin and glutelin fractions. Glutelin was the major fraction with ~53% of the nut storage proteins containing at least 21 peptides with different putative biological activities, including antihypertensives, antioxidants, immunomodulators, protease inhibitors, and inhibitors of cell cycle progression in cancer cells. Data showed that using 50 μg/mL tryptic digests of enriched peptides obtained from nut glutelins is able to induce up to 19% of apoptosis in both HeLa and CasKi cervical cancer cells. To our knowledge, this is the first report that shows the potential value of the nut-encoded peptides to be considered as adjuvants in cancer therapies.

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A novel non-phosphorylated potential antitumoral peptide inhibits STAT3 biological activity☆

Cited by 10 publications

References 42 publications

The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death

The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death

Design, synthesis, and in vitro characterization of novel hybrid peptidomimetic inhibitors of STAT3 protein

Characterization and Identification of Cryptic Biopeptides inCarya illinoinensis(Wangenh K. Koch) Storage Proteins

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