Control of a tumor suppressor PDCD4: Degradation mechanisms of the protein in hepatocellular carcinoma cells

Matsuhashi, Sachiko; Hamajima, Hiroshi; Xia, Jinghe; Zhang, Hao; Mizuta, Toshihiko; Anzai, Keizo; Ozaki, Iwata

doi:10.1016/j.cellsig.2013.11.038

Cited by 25 publications

(32 citation statements)

References 27 publications

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“…We previously showed that PDCD4 protein was phosphorylated at S67, S71, and S76 via the tumor promotor EGF and TPA-mediated signaling pathways and degraded by the ubiquitin-proteasome system [25,26]. While investigating the degradation mechanisms of PDCD4 protein mediated by tumor promotors, we repeatedly observed that EGF upregulated the PDCD4 protein levels in the presence of the proteasome inhibitor MG132 in Huh7 hepatoma cells, as shown in Figure 1.…”

Section: The Autophagy Inhibitors Bafilomycin A1 and 3-methyladenine mentioning

confidence: 68%

“…The TPA-activated PKCδ and PKCε signaling pathways phosphorylate PDCD4, leading to its degradation by the proteasome system in Huh7 hepatocellular carcinoma cells [18,25,26]. During the investigation of PDCD4 degradation mechanisms, we found that the proteasome inhibitor MG132 slightly upregulated the PDCD4 protein levels in Huh7 cells [26]. It led us to assume the presence of different regulatory pathways of this protein.…”

Section: Introductionmentioning

confidence: 93%

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Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy

Manirujjaman

Ozaki

Murata

et al. 2020

Cells

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PDCD4 (programmed cell death 4) is a tumor suppressor that plays a crucial role in multiple cellular functions, such as the control of protein synthesis and transcriptional control of some genes, the inhibition of cancer invasion and metastasis. The expression of this protein is controlled by synthesis, such as via transcription and translation, and degradation by the ubiquitin-proteasome system. The mitogens, known as tumor promotors, EGF (epidermal growth factor) and TPA (12-O-tetradecanoylphorbol-13-acetate) stimulate the degradation of PDCD4 protein. However, the whole picture of PDCD4 degradation mechanisms is still unclear, we therefore investigated the relationship between PDCD4 and autophagy. The proteasome inhibitor MG132 and the autophagy inhibitor bafilomycin A1 were found to upregulate the PDCD4 levels. PDCD4 protein levels increased synergistically in the presence of both inhibitors. Knockdown of p62/SQSTM1 (sequestosome-1), a polyubiquitin binding partner, also upregulated the PDCD4 levels. P62 and LC3 (microtubule-associated protein 1A/1B-light chain 3)-II were co-immunoprecipitated by an anti-PDCD4 antibody. Colocalization particles of PDCD4, p62 and the autophagosome marker LC3 were observed and the colocalization areas increased in the presence of autophagy and/or proteasome inhibitor(s) in Huh7 cells. In ATG (autophagy related) 5-deficient Huh7 cells in which autophagy was impaired, the PDCD4 levels were increased at the basal levels and upregulated in the presence of autophagy inhibitors. Based on the above findings, we concluded that after phosphorylation in the degron and ubiquitination, PDCD4 is degraded by both the proteasome and autophagy systems.

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Section: The Autophagy Inhibitors Bafilomycin A1 and 3-methyladenine mentioning

confidence: 68%

Section: Introductionmentioning

confidence: 93%

Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy

Manirujjaman

Ozaki

Murata

et al. 2020

Cells

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“…It has also been reported that PDCD4 could inhibit cell invasion in breast cancer by suppressing metalloproteinase 2. 31,32 These results indicate that emphasis should be placed on an exploration of the relationship between PDCD4 and miR-155, which may cast light on the pathogenesis of NSCLC.…”

Section: Discussionmentioning

confidence: 97%

MiR‐155 inhibits proliferation and invasion by directly targeting PDCD4 in non‐small cell lung cancer

Feng

Song

et al. 2017

Thoracic Cancer

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BackgroundMicroRNAs are often abnormally expressed in human non‐small cell lung cancer (NSCLC) and are thought to play a critical role in the emergence or maintenance of NSCLC by binding to its target messenger RNA. We assessed the effects of miR‐155 on cell proliferation and invasion to elucidate the role played by miR‐155/PDCD 4 in NSCLC.MethodsQuantitative reverse transcription‐PCR, Western blotting, and cell counting kit‐8, luciferase, and transwell invasion assays were conducted on a normal human bronchial epithelial cell line (BEAS‐2B) and three NSCLC cell lines (SPC‐A‐1, A549, and H2170).ResultsWe confirmed that miR‐155 was upregulated, while PDCD 4 messenger RNA and protein levels were downregulated in NSCLC cell lines. miR‐155 negatively regulated PDCD 4 at both transcriptional and post‐transcriptional levels. Moreover, PDCD 4 was forecast as an assumed target of miR‐155 using bioinformatic methods and we demonstrated that PDCD 4 was a direct target of miR‐155 using luciferase reporter assays. Furthermore, PDCD 4 overexpression could restrain NSCLC proliferation and invasion induced by miR‐155.ConclusionOur results collectively demonstrate that miR‐155 exerts an oncogenic role in NSCLC by directly targeting PDCD 4.

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“…22,47,48 It performs an important function in tumor invasion and metastasis through inhibition of STAT3 activation, which are known to be involved in cancer progression. 22,[47][48][49] Our data suggested that PDCD4 expression has a negative correlation with the expression of miR-21 in SACC tissues and cell lines at protein level. Applying specific inhibitor of miR-21 can rescue PDCD4 expression, negatively regulated SACC cell invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma

Jiang

Hou

et al. 2015

Laboratory Investigation

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miR-21, which is a putative tumor onco-miR and frequently overexpressed microRNA in various tumors, has been linked to tumor progression through targeting of tumor-suppressor genes. In this study, we sought to determine whether miR-21 has any role on tumor progression of salivary adenoid cystic carcinoma (SACC) and the possible mechanisms. We found that the level of miR-21 expression was significantly higher in SACC than that in normal salivary tissues, and it is also higher in tumors with metastasis than that without metastasis. Using an anti-miR-21 inhibitor in an in vitro model, downregulation of miR-21 significantly decreased the capacity of invasion and migration of SACC cells, whereas a pre-miR-21 increased the capacity of invasion and migration of SACC cells. To explore the potential mechanisms by which miR-21 regulate invasion and migration, we identified one direct miR-21 target gene, programmed cell death 4 (PDCD4), which has been implicated in invasion and metastasis Salivary adenoid cystic carcinoma (SACC) is one of the most common malignancy of the salivary gland, accounting for 10% of salivary gland tumors and 30% of human salivary gland malignancies. 1,2 SACC is characterized by slow but aggressive growth, nerve and blood vessel invasion, multiple recurrences, and distant metastases. 3-5 Lung metastasis and nerve metastasis are the biological characteristics of SACC. [6][7][8] It has been reported that the incidence of SACC with distant metastasis ranged from 35 to 50% of all cases. Lung was the most common organ of its distant metastasis, and lung metastasis is still the leading death cause of patients with SACC. 4,5 Although the 5-year survival rate is high for patients with SACC, probably because of the slow growth of the tumor, the 10-and 15-year prognoses are poor because of the frequent local recurrences and distant metastases. [6][7][8] Although multiple genetic and epigenetic alterations have been detected in SACC, 3,9-13 the precise molecular mechanisms of progression and metastasis of SACC remain unknown.MicroRNAs (miRNAs) are small non-coding RNA molecules, with a length of 20-22 nucleotides, that regulate gene expression by either translational inhibition or mRNA degradation. miRNAs function as either oncogenes or tumor suppressors by inhibiting the expression of target genes, some of which are either directly or indirectly involved with canonical signaling pathways. 13,14 The roles and function of some selected miRNAs in SACC have been reported. 15

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Control of a tumor suppressor PDCD4: Degradation mechanisms of the protein in hepatocellular carcinoma cells

Cited by 25 publications

References 27 publications

Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy

Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy

MiR‐155 inhibits proliferation and invasion by directly targeting PDCD4 in non‐small cell lung cancer

miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma

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