Regulation of tumor suppressor PDCD4 by novel protein kinase C isoforms
Open accessAbstract
Transforming growth factor-beta1 (TGF-beta1) induces apoptosis in normal hepatocytes and hepatoma cells. PDCD4 is involved in TGF-beta1-induced apoptosis via the Smad pathway. The tumor promoter 12-O-tetradecanoylphorbor-13-acetate (TPA), a protein kinase C stimulator, inhibits TGF-beta1-induced apoptosis. However, the mechanisms of TPA action on PDCD4 expression remain to be elucidated. Therefore. the regulatory mechanism of PDCD4 expression by PKC was investigated. The treatment of the human hepatoma cell line, Huh7 with TPA suppressed PDCD4 protein expression and TGF-beta1 failed to increase the PDCD4 protein expression. PKC inhibitors Ro-31-8425 or bisindolylmaleimide-1-hydrocholoride (pan-PKC inhibitors) and rottlerin (PKCdelta inhibitor), but not Go6976 (PKCalpha inhibitor), enhanced the induction of PDCD4 protein by TGF-beta1. Furthermore, siRNA-mediated knockdown of PKCdelta and epsilon, but not PKCalpha, augmented the TGF-beta1-stimulated PDCD4 protein expression. However, TPA or pan-PKC inhibitor did not alter the PDCD4 mRNA expression either under basal- and TGF-beta1-treated conditions. The down-regulation of PDCD4 by TPA was restored by treatment with the proteasome inhibitor MG132. These data suggest that two isoforms of PKCs are involved in the regulation of the PDCD4 protein expression related to the proteasomal degradation pathway.
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TPA inhibits TGF-β1-induced apoptosis down-regulating PDCD4 expression but does not stimulate phosphorylation of Akt and S6K1.
“TPA also inhibits the TGF-β1-induced apoptosis down-regulating PDCD4 expression but does not stimulate the phosphorylation of Akt and S6K1.”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [68]
Section 3.1 reports that TPA reduced TGF-β1-induced apoptosis and PDCD4 protein expression in Huh7 cells. But Section 3.2 (Fig. 3C) says TPA slightly stimulated phosphorylation of both Akt and S6K, contrary to the claim that it did not stimulate them. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredPRCKδ and PRCKε knockdown up-regulated PDCD4 expression, but PRCKα knockdown did not change PDCD4 expression.
“siRNA-mediated knockdown of the PRCKs showed that PRCKδ and PRCKε knockdown up-regulated, but PRCKα did not change PDCD4 expression [68].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [68]
The mTOR inhibitor rapamycin does not inhibit TPA-induced PDCD4 suppression in Huh7 hepatoma cells.
“The mTOR inhibitor rapamycin does not inhibit the TPA-induced PDCD4 suppression in Huh7 hepatoma cells [68] (Figure 5).”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [68]
EGF and TPA suppress PDCD4 protein levels through different signaling pathways in Huh7 cells.
“From these results, it was concluded that EGF and TPA suppress PDCD4-protein levels through different signaling pathways in Huh7 cells.”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [68]
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- Authors
- Nakashima, M., Hamajima, H., Xia, J., Iwane, S., Kwaguchi, Y., Eguchi, Y., Mizuta, T., Fujimoto, K., Ozaki, I., & Matsuhashi, S.
- Affiliations
- Saga University (JP)
- Corresponding author
- Ozaki, Iwata
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 1803
- Issue
- 9
- Pages
- 1020-1027
- ISSN
- 0167-4889 (ISSN-L)
- OpenAlex
- W2042697056
- Cited by
- 17
- References
- 51
- Citations by year
- 2025: 3 · 2021: 1 · 2020: 2 · 2019: 1 · 2016: 1 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 2
- FWCI
- 0.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1086 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- PDCD4, PKC isoforms, PKCδ, protein kinase C epsilon, TGF-β1, apoptosis, Smad signaling, hepatoma cells, tissue plasminogen activator, proteasomal degradation, protein stability, tumor suppressor regulation
- MeSH terms
- Enzyme Inhibitors, Humans, Isoenzymes, Protein Kinase C, Tetradecanoylphorbol Acetate, Signal Transduction, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, RNA-Binding Proteins, Phosphatidylinositol 3-Kinases, RNA, Small Interfering, Cell Line, Tumor, Proteasome Endopeptidase Complex, Cell Proliferation, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-akt, Transforming Growth Factor beta1, Proteasome Inhibitors
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