Diaryl Disulfides as Novel Stabilizers of Tumor Suppressor Pdcd4
Open accessAbstract
The translation inhibitor and tumor suppressor Pdcd4 was reported to be lost in various tumors and put forward as prognostic marker in tumorigenesis. Decreased Pdcd4 protein stability due to PI3K-mTOR-p70S6K1 dependent phosphorylation of Pdcd4 followed by β-TrCP1-mediated ubiquitination, and proteasomal destruction of the protein was characterized as a major mechanism contributing to the loss of Pdcd4 expression in tumors. In an attempt to identify stabilizers of Pdcd4, we used a luciferase-based high-throughput compatible cellular assay to monitor phosphorylation-dependent proteasomal degradation of Pdcd4 in response to mitogen stimulation. Following a screen of approximately 2000 compounds, we identified 1,2-bis(4-chlorophenyl)disulfide as a novel Pdcd4 stabilizer. To determine an initial structure-activity relationship, we used 3 additional compounds, synthesized according to previous reports, and 2 commercially available compounds for further testing, in which either the linker between the aryls was modified (compounds 2-4) or the chlorine residues were replaced by groups with different electronic properties (compounds 5 and 6). We observed that those compounds with alterations in the sulfide linker completely lost the Pdcd4 stabilizing potential. In contrast, modifications in the chlorine residues showed only minor effects on the Pdcd4 stabilizing activity. A reporter with a mutated phospho-degron verified the specificity of the compounds for stabilizing the Pdcd4 reporter. Interestingly, the active diaryl disulfides inhibited proliferation and viability at concentrations where they stabilized Pdcd4, suggesting that Pdcd4 stabilization might contribute to the anti-proliferative properties. Finally, computational modelling indicated that the flexibility of the disulfide linker might be necessary to exert the biological functions of the compounds, as the inactive compound appeared to be energetically more restricted.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Diaryl disulfides stabilize PDCD4 protein.
“They have identified diaryl disulfides [98] and isolated tricyclic guanidine alkaloids from the marine animal sponge [99] as the PDCD4-protein stabilizer (Table 3).”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [98]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
S6K1- and ßTRCP-Mediated Degradation of PDCD4 Promotes Protein Translation and Cell Growth
Dorrello, N. V., Peschiaroli, A., Guardavaccaro, D., Colburn, N. H., Sherman, N. E., & Pagano, M. (2006) · Science · doi:10.1126/science.1130276 · Cited by 731 · see citing works
Self-citationYang, H.-S., Jansen, A. P., Komar, A. A., Zheng, X., Merrick, W. C., Costes, S., Lockett, S. J., Sonenberg, N., & Colburn, N. H. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.1.26-37.2003 · Cited by 494 · see citing works
Self-citationIsolation of a novel mouse gene MA-3 that is induced upon programmed cell death
Shibahara, K., Asano, M., Ishida, Y., Aoki, T., Koike, T., & Honjo, T. (1995) · Gene · doi:10.1016/0378-1119(95)00607-9 · Cited by 223 · see citing works
Epidermal Expression of the Translation Inhibitor Programmed Cell Death 4 Suppresses Tumorigenesis
Jansen, A. P., Camalier, C. E., & Colburn, N. H. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-2119 · Cited by 212 · see citing works
Self-citationMudduluru, G., Medved, F., Grobholz, R., Jost, C., Gruber, A., Leupold, J. H., Post, S., Jansen, A., Colburn, N. H., & Allgayer, H. (2007) · Cancer · doi:10.1002/cncr.22983 · Cited by 196 · see citing works
Self-citationTranslational Regulation of Autoimmune Inflammation and Lymphoma Genesis by Programmed Cell Death 4
Hilliard, A., Hilliard, B., Zheng, S.-J., Sun, H., Miwa, T., Song, W., Göke, R., & Chen, Y. H. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.11.8095 · Cited by 167 · see citing works
Efficient synthesis of disulfides by air oxidation of thiols under sonication
Ruano, J. L. G., Parra, A., & Alemán, J. (2008) · Green Chemistry · doi:10.1039/b800705e · Cited by 164 · see citing works
Leupold, J. H., Yang, H.-S., Colburn, N. H., Asangani, I., Post, S., & Allgayer, H. (2007) · Oncogene · doi:10.1038/sj.onc.1210234 · Cited by 163 · see citing works
Self-citationPdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation
Yang, H.-S., Knies, J. L., Stark, C., & Colburn, N. H. (2003) · Oncogene · doi:10.1038/sj.onc.1206433 · Cited by 160 · see citing works
Self-citationTranslation Inhibitor Pdcd4 Is Targeted for Degradation during Tumor Promotion
Schmid, T., Jansen, A. P., Baker, A. R., Hegamyer, G., Hagan, J. P., & Colburn, N. H. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-1719 · Cited by 151 · see citing works
Self-citationOba, M., Tanaka, K., Nishiyama, K., & Andō, W. (2011) · The Journal of Organic Chemistry · doi:10.1021/jo200496r · Cited by 149 · see citing works
Wang, Q., Sun, Z., & Yang, H. (2007) · Oncogene · doi:10.1038/sj.onc.1210793 · Cited by 147 · see citing works
Jansen, A. P., Camalier, C. E., Stark, C., & Colburn, N. H. (2004) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.103.3.2 · Cited by 132 · see citing works
Self-citationPdcd4, a colon cancer prognostic that is regulated by a microRNA
Allgayer, H. (2009) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2009.09.001 · Cited by 123 · see citing works
Gilbert, A. M., Failli, A. A., Shumsky, J. S., Yang, Y., Severin, A. I., Singh, G., Hu, W. K., Keeney, D. R., Petersen, P. J., & Katz, A. H. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm060499t · Cited by 103 · see citing works
White, K., Dempsie, Y., Caruso, P. L., Wallace, E., McDonald, R. A., Stevens, H., Hatley, M. E., van Rooij, E., Morrell, N. W., MacLean, M. R., et al. (2014) · Hypertension · doi:10.1161/hypertensionaha.113.03037 · Cited by 92 · see citing works
van den Nieuwendijk, A. M. C. H., Pietra, D., Heitman, L. H., Göblyös, A., & IJzerman, A. P. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm030863d · Cited by 84 · see citing works
Loss of Programmed cell death 4 (Pdcd4) associates with the progression of ovarian cancer
Wei, N., Liu, S. S., Leung, T. H., Tam, K., Liao, X. Y., Cheung, A., Chan, K. K. L., & Ngan, H. (2009) · Molecular Cancer · doi:10.1186/1476-4598-8-70 · Cited by 79 · see citing works
Blees, J. S., Bokesch, H. R., Rübsamen, D., Schulz, K. L., Milke, L., Bajer, M. M., Gustafson, K. R., Henrich, C. J., McMahon, J. B., Colburn, N. H., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046567 · Cited by 63 · see citing works
Self-citationGrkovic, T., Blees, J. S., Colburn, N. H., Schmid, T., Thomas, C. L., Henrich, C. J., McMahon, J. B., & Gustafson, K. R. (2011) · Journal of Natural Products · doi:10.1021/np100918z · Cited by 60 · see citing works
Self-citationZhao, L., Huang, S., Tang, S., Jiang, C., Duan, Y., Beutler, J. A., Henrich, C. J., McMahon, J. B., Schmid, T., Blees, J. S., et al. (2011) · Journal of Natural Products · doi:10.1021/np200603g · Cited by 51 · see citing works
Self-citationHwang, S.-K., Jin, H., Kwon, J. T., Chang, S.-H., Kim, T. H., Cho, C.-S., Lee, K. H., Young, M. R., Colburn, N. H., Beck, G. R., et al. (2007) · Gene Therapy · doi:10.1038/sj.gt.3302983 · Cited by 44 · see citing works
Self-citationInflammation-induced loss of Pdcd4 is mediated by phosphorylation-dependent degradation
Schmid, T., Bajer, M. M., Blees, J. S., Eifler, L. K., Milke, L., Rübsamen, D., Schulz, K., Weigert, A., Baker, A. R., Colburn, N. H., et al. (2011) · Carcinogenesis · doi:10.1093/carcin/bgr131 · Cited by 39 · see citing works
Self-citationCharacterization of pomiferin triacetate as a novel mTOR and translation inhibitor
Bajer, M. M., Kunze, M. M., Blees, J. S., Bokesch, H. R., Chen, H., Brauß, T. F., Dong, Z., Gustafson, K. R., Biondi, R. M., Henrich, C. J., et al. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.034 · Cited by 17 · see citing works
Self-citationBlees, J. S., Schmid, T., Thomas, C. L., Baker, A. R., Benson, L. C., Evans, J. R., Goncharova, E. I., Colburn, N. H., McMahon, J. B., & Henrich, C. J. (2009) · SLAS DISCOVERY · doi:10.1177/1087057109351028 · Cited by 17 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions
Matsuhashi, S., Manirujjaman, M., Hamajima, H., & Ozaki, I. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092304 · Cited by 143 · see citing works
Sąsiadek, W., Bryndal, I., Lis, T., Wandas, M., & Hanuza, J. (2022) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2022.132535 · Cited by 15 · see citing works
Phytotoxicity Study of Ortho-Disubstituted Disulfides and Their Acyl Derivatives
Oliveira, S. C. C., Andrade, C. K. Z., Varela, R. M., Molinillo, J. M. G., & Macías, F. A. (2019) · ACS Omega · doi:10.1021/acsomega.8b03219 · Cited by 14 · see citing works
Synthesis and biological properties of a series of aryl alkyl disulfide derivatives
Joondan, N., Inassee, M. A. T., Bhowon, M. G., & Laulloo, S. J. (2020) · Heliyon · doi:10.1016/j.heliyon.2020.e05368 · Cited by 9 · see citing works
Solvent free, palladium catalyzed highly facile synthesis of diaryl disulfides from aryl thiols
Dutta, P. K., Majumder, A., Dutta, S., Dhar, B. B., Munshi, P., & Sen, S. (2016) · Tetrahedron Letters · doi:10.1016/j.tetlet.2016.12.074 · Cited by 8 · see citing works
Skrickus, K., Šiugždaitė, J., Lelešius, R., Anusevičius, K., Grybaitė, B., Vaickelionienė, R., & Mickevičius, V. (2023) · ChemistrySelect · doi:10.1002/slct.202300332 · Cited by 5 · see citing works
Jana, K., Bandyopadhyay, T., & Ganguly, B. (2017) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2017.10.006 · Cited by 4 · see citing works
Nantes, C. I., Pereira, I. D., Bai, R., Hamel, E., Burnett, J. C., Oliveira, R. J., Matos, M. D. F. C., Beatriz, A., Yonekawa, M. K. A., Perdomo, R. T., et al. (2019) · ChemMedChem · doi:10.1002/cmdc.201900566 · Cited by 4 · see citing works
Chen, S., Chiu, C., Hung, C., Pan, W., Chen, Y., Bow, Y., Li, W., Hsu, S., Lin, I., Wen, Z., et al. (2023) · Environmental Toxicology · doi:10.1002/tox.23828 · Cited by 4 · see citing works
Skrickus, K., Šiugždaitė, J., Lelešius, R., Anusevičius, K., Grybaitė, B., Vaickelionienė, R., & Mickevičius, V. (2022) · Research Square · doi:10.21203/rs.3.rs-2397833/v1
- Authors
- Schmid, T., Blees, J. S., Bajer, M. M., Wild, J., Pescatori, L., Cuzzucoli Crucitti, G., Scipione, L., Costi, R., Henrich, C. J., Brüne, B., Colburn, N. H., & Di Santo, R.
- Affiliations
- Goethe University Frankfurt (DE)
- Istituto Pasteur (IT)
- Frederick National Laboratory for Cancer Research (US)
- Corresponding author
- Schmid, Tobias
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-03-16
- Volume
- 11
- Issue
- 3
- Pages
- e0151643
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4794182
- OpenAlex
- W2298225921
- Cited by
- 10
- References
- 25
- Citations by year
- 2023: 2 · 2022: 2 · 2020: 1 · 2019: 3 · 2017: 1 · 2016: 1
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- Locations
- PLoS ONE (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Publikationsdatenbank der Fraunhofer-Gesellschaft (Fraunhofer-Gesellschaft) (submittedVersion, other-oa)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
- Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
- Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
- Funders
- Frederick National Laboratory for Cancer Research (HHSN261200800001E.)
- Deutsche Forschungsgemeinschaft (SCHM2663, HHSN261200800001E, GRK1172, SCHM 2663/3)
- National Institutes of Health (#HHSN261200800001E, HHSN261200800001C)
- National Cancer Institute (HHSN261200800001E))
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- PDCD4, diaryl disulfides, protein stabilization, tumor suppressor, β-TrCP1, proteasomal degradation, structure-activity relationship, antiproliferative activity, structure-based drug design
- MeSH terms
- Cell Cycle, Humans, Structure-Activity Relationship, Sulfides, RNA-Binding Proteins, Tumor Suppressor Proteins, Cell Proliferation, Apoptosis Regulatory Proteins, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
