Regulation of PSMB5 Protein and β Subunits of Mammalian Proteasome by Constitutively Activated Signal Transducer and Activator of Transcription 3 (STAT3)

Vangala, Janakiram R.; Dudem, Srikanth; Jain, Nishant; Kalivendi, Shasi V.

doi:10.1074/jbc.m113.542829

Cited by 61 publications

(54 citation statements)

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“…It is activated in several cancer cell types and has been shown to up-regulate several β sub-units of the 20S proteasome. 98 Prostate cancer cells with activated STAT3 at baseline displayed a decrease of proteasome sub-unit PSMB5 mRNA and protein levels when STAT3 was dephosphorylated by inhibitors Stattic and WP1066, and thus, inactivated. Such response was not observed in another prostate cancer cell line without baseline STAT3 activation.…”

Section: Rbx1mentioning

confidence: 99%

“…Of interest, STAT3 is activated in CSCs, 99 and this implies that additional signals suppress the expression of proteasome sub-units in these cells, which become de-repressed in the differentiated progeny, or alternatively, additional activating signals up-regulate proteasome units in these progeny cells. 19S sub-units or α ring units of the 20S proteasome and their regulation by STAT3 were not specifically investigated in the above study 98 or any other studies, but multiple STAT3 binding sites are present in all components promoters as checked in the Transcriptional Regulatory Element Database (TRED) and JASPAR databases (see later). STAT3 is also involved in cancer cachexia by stimulating proteolysis through activation of both the proteasome and apoptosis-related protease caspase 3 in muscle of cancer-bearing animals.…”

Section: Rbx1mentioning

confidence: 99%

“…Such response was not observed in another prostate cancer cell line without baseline STAT3 activation. 98 Thus, in certain cancers, STAT3 pathway activation may contribute to proteasome up-regulation down-stream of growth factors. Of interest, STAT3 is activated in CSCs, 99 and this implies that additional signals suppress the expression of proteasome sub-units in these cells, which become de-repressed in the differentiated progeny, or alternatively, additional activating signals up-regulate proteasome units in these progeny cells.…”

Section: Rbx1mentioning

confidence: 99%

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Proteasome expression and activity in cancer and cancer stem cells

Voutsadakis

2017

Tumour Biol.

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Proteasome is a multi-protein organelle that participates in cellular proteostasis by destroying damaged or short-lived proteins in an organized manner guided by the ubiquitination signal. By being in a central place in the cellular protein complement homeostasis, proteasome is involved in virtually all cell processes including decisions on cell survival or death, cell cycle, and differentiation. These processes are important also in cancer, and thus, the proteasome is an important regulator of carcinogenesis. Cancers include a variety of cells which, according to the cancer stem cell theory, descend from a small percentage of cancer stem cells, alternatively termed tumor-initiating cells. These cells constitute the subsets that have the ability to propagate the whole variety of cancer and repopulate tumors after cytostatic therapies. Proteasome plays a role in cellular processes in cancer stem cells, but it has been found to have a decreased function in them compared to the rest of cancer cells. This article will discuss the transcriptional regulation of proteasome sub-unit proteins in cancer and in particular cancer stem cells and the relationship of the proteasome with the pluripotency that is the defining characteristic of stem cells. Therapeutic opportunities that present from the understanding of the proteasome role will also be discussed.

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Section: Rbx1mentioning

confidence: 99%

Section: Rbx1mentioning

confidence: 99%

Section: Rbx1mentioning

confidence: 99%

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Proteasome expression and activity in cancer and cancer stem cells

Voutsadakis

2017

Tumour Biol.

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“…In cancer, however, malignant cells might also acquire the capacity to induce autophagy of the mesenchymal cells in tumor stroma, to supply nutrients and generate a niche that fosters cancer cell survival and proliferation. 114,115 Thereby, STAT3 regulates proteostasis through the proteasome, a module that interacts with autophagy as we see next. For example, in response to ATP deficiency, AMPK is activated and induces autophagy through inhibition of the mammalian target of rapamycin.…”

Section: Cq Regulates Tissue Responses To Metabolic and Inflammatory mentioning

confidence: 93%

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

2019

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Chloroquines are 4-aminoquinoline-based drugs mainly used to treat malaria. At pharmacological concentrations, they have significant effects on tissue homeostasis, targeting diverse signaling pathways in mammalian cells. A key target pathway is autophagy, which regulates macromolecule turnover in the cell. In addition to affecting cellular metabolism and bioenergetic flow equilibrium, autophagy plays a pivotal role at the interface between inflammation and cancer progression. Chloroquines consequently have critical effects in tissue metabolic activity and importantly, in key functions of the immune system. In this article, we will review the work addressing the role of chloroquines in the homeostasis of mammalian tissue, and the potential strengths and weaknesses concerning their use in cancer therapy.

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“…The 3 protease activities, C-L, T-L and CT-L activity, are mediated by the three proteolytically active subunits, the β1, β2 and β5 subunits, respectively [29] . In general, proteasome activities are inhibited by direct binding interactions between putative proteasome inhibitors and the active proteasome β subunits.…”

Section: Discussionmentioning

confidence: 99%

Bufalin derivative BF211 inhibits proteasome activity in human lung cancer cells in vitro by inhibiting β1 subunit expression and disrupting proteasome assembly

et al. 2016

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Aim: Bufalin is one of the active components in the traditional Chinese medicine ChanSu that is used to treat arrhythmia, inflammation and cancer. BF211 is a bufalin derivative with stronger cytotoxic activity in cancer cells. The aim of this study was to identify the putative target proteins of BF211 and the signaling pathways in cancer cells. Methods: A549 human lung cancer cells were treated with BF211. A SILAC-based proteomic analysis was used to detect the protein expression profiles of BF211-treated A549 cells. Cellular proteasome activities were examined using fluorogenic peptide substrates, and the binding affinities of BF211 to recombinant proteasome subunit proteins were evaluated using the Biacore assay. The expression levels of proteasome subunits were determined using RT-PCR and Western blotting, and the levels of the integral 26S proteasome were evaluated using native PAGE analysis. Results: The proteomic analysis revealed that 1282 proteins were differentially expressed in BF211-treated A549 cells, and the putative target proteins of BF211 were associated with various cellular functions, including transcription, translation, mRNA splicing, ribosomal protein synthesis and proteasome function. In A549 cells, BF211 (5, 10, and 20 nmol/L) dose-dependently inhibited the enzymatic activities of proteasome. But BF211 displayed a moderate affinity in binding to proteasome β1 subunit and no binding affinity to the β2 and β5 subunits. Moreover, BF211 (0.1, 1, and 10 nmol/L) did not inhibit the proteasome activities in the cell lysates. BF211 (5, 10, and 20 nmol/L) significantly decreased the expression level of proteasome β1 subunit and the levels of integral 26S proteasome in A549 cells. Similarly, knockdown of the β1 subunit with siRNA in A549 cells significantly decreased integral 26S proteasome and proteasome activity. Conclusion: BF211 inhibits proteasome activity in A549 cells by decreasing β1 subunit expression and disrupting proteasome assembly.Keywords: bufalin; ChanSu; cardiac steroids; proteasome β1 subunit; proteasome assembly; A549 human lung cancer cells; In the present study, to identify the possible signaling network activated by BF211 in cancer cells, we conducted a SILAC-based proteomic analysis and compared the protein expression profiles of A549 human lung cancer cells treated with either BF211 or a solvent control. Our findings suggested that BF211 influences proteasome function, and we further evaluated the effects and potential mechanisms mediating this phenomenon.

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Regulation of PSMB5 Protein and β Subunits of Mammalian Proteasome by Constitutively Activated Signal Transducer and Activator of Transcription 3 (STAT3)

Cited by 61 publications

References 50 publications

Proteasome expression and activity in cancer and cancer stem cells

Proteasome expression and activity in cancer and cancer stem cells

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

Bufalin derivative BF211 inhibits proteasome activity in human lung cancer cells in vitro by inhibiting β1 subunit expression and disrupting proteasome assembly

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