Molecular chaperone CCT3 supports proper mitotic progression and cell proliferation in hepatocellular carcinoma cells

Zhang, Yuanyuan; Wang, Yuqi; Wei, Youheng; Wu, Jiaxue; Zhang, Pingzhao; Shen, Suqin; Saiyin, Hexige; Wumaier, Reziya; Yang, Xiaosong; Wang, Chenji; Liu, Yu

doi:10.1016/j.canlet.2015.12.029

Cited by 70 publications

(76 citation statements)

References 38 publications

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“…TRiC additionally contributes obligatory growth/survival functions in breast (Guest et al, 2015) and liver (Zhang et al, 2016) cancers. This complex is highly likely to contribute to the altered cytoskeletal properties and rounded phenotype of DM cells.…”

Section: Discussionmentioning

confidence: 99%

PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

Thejer

Adhikary

Kaur

et al. 2019

Preprint

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Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. It contains phosphorylated tyrosines which evolutionarily preceded deuterostome gastrulation and tissue differentiation mechanisms. Here, we demonstrate that manipulating PGRMC1 phosphorylation status in MIA PaCa-2 (MP) cells imposes broad pleiotropic effects.Relative to parental cells over-expressing hemagglutinin-tagged wild-type (WT) PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant (DM) exhibited reduced levels of proteins involved in energy metabolism and mitochondrial function, and altered glucose metabolism suggesting modulation of the Warburg effect.This was associated with increased PI3K/Akt activity, altered cell shape, actin cytoskeleton, motility, and mitochondrial properties. An S57A/Y180F/S181A triple mutant (TM) indicated the involvement of Y180 in PI3K/Akt activation. Mutation of Y180F strongly attenuated mouse xenograft tumor growth. An accompanying paper demonstrates altered metabolism, mutation incidence, and epigenetic status in these cells, indicating that PGRMC1 phosphorylation strongly influences cancer biology.

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Section: Discussionmentioning

confidence: 99%

PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

Thejer

Adhikary

Kaur

et al. 2019

Preprint

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“…CCT3 depletion suppresses cell proliferation by inducing mitotic arrest at prometaphase and apoptosis eventually in HCC in vitro . Clinically, overexpression of CCT3 predicts poor prognosis in hepatocellular carcinoma patients after hepatectomy [25, 26]. CCT3 is significantly associated with carboplatin resistance in ovarian cancer patients after surgery treatment [27].…”

Section: Discussionmentioning

confidence: 99%

Identification of the Key Genes and Pathways in Esophageal Carcinoma

Zhang

et al. 2016

Gastroenterology Research and Practice

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Objective. Esophageal carcinoma (EC) is a frequently common malignancy of gastrointestinal cancer in the world. This study aims to screen key genes and pathways in EC and elucidate the mechanism of it. Methods. 5 microarray datasets of EC were downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) were screened by bioinformatics analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction (PPI) network construction were performed to obtain the biological roles of DEGs in EC. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the expression level of DEGs in EC. Results. A total of 1955 genes were filtered as DEGs in EC. The upregulated genes were significantly enriched in cell cycle and the downregulated genes significantly enriched in Endocytosis. PPI network displayed CDK4 and CCT3 were hub proteins in the network. The expression level of 8 dysregulated DEGs including CDK4, CCT3, THSD4, SIM2, MYBL2, CENPF, CDCA3, and CDKN3 was validated in EC compared to adjacent nontumor tissues and the results were matched with the microarray analysis. Conclusion. The significantly DEGs including CDK4, CCT3, THSD4, and SIM2 may play key roles in tumorigenesis and development of EC involved in cell cycle and Endocytosis.

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“…another class of protein-folding complexes, called chaperonins, gained interest with the recognition that cancer cells highly express these mediators of protein-folding [14][15][16][17][18][19][20][21][22][23] . The cytosolic, eukaryotic chaperonin-containing TCP-1 (CCT) is an emerging player in neoplastic transformation with potential for development as a novel diagnostic marker and therapeutic target.…”

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confidence: 99%

Investigating Chaperonin-Containing TCP-1 subunit 2 as an essential component of the chaperonin complex for tumorigenesis

Showalter

Martini

Nierenberg

et al. 2020

Sci Rep

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Chaperonin-containing TCP-1 (CCT or TRiC) is a multi-subunit complex that folds many of the proteins essential for cancer development. CCT is expressed in diverse cancers and could be an ideal therapeutic target if not for the fact that the complex is encoded by eight distinct genes, complicating the development of inhibitors. Few definitive studies addressed the role of specific subunits in promoting the chaperonin's function in cancer. To this end, we investigated the activity of CCT2 (CCTβ) by overexpressing or depleting the subunit in breast epithelial and breast cancer cells. We found that increasing total CCT2 in cells by 1.3-1.8-fold using a lentiviral system, also caused CCT3, CCT4, and CCT5 levels to increase. Likewise, silencing cct2 gene expression by ~50% caused other CCT subunits to decrease. Cells expressing CCT2 were more invasive and had a higher proliferative index. CCT2 depletion in a syngeneic murine model of triple negative breast cancer (TNBC) prevented tumor growth. These results indicate that the CCT2 subunit is integral to the activity of the chaperonin and is needed for tumorigenesis. Hence CCT2 could be a viable target for therapeutic development in breast and other cancers. The hallmarks of cancer (uncontrolled proliferation, genomic instability, metastasis, etc.) reveal the complex nature of this disease and the challenges faced developing effective therapeutics 1,2. Cancer does, however, have an "Achilles heel" and that is its dependency or addiction on major cellular events or processes like transcription, translation, splicing, protein degradation and protein-folding 3. In healthy cells, such conserved and essential processes are rigorously regulated by the proteostasis network (PN) to ensure proteome balance. In order to maintain proteome integrity, the cellular proteome must be synthesized, folded into its native structure, and, when no longer needed, degraded and the amino acids recycled 4,5. Chaperones and chaperonins are key players in the PN 6. Unlike healthy, non-transformed cells, the PN of cancer cells is taxed to produce proteins involved in survival, angiogenesis, migration, proliferation which are essential for tumor formation, progression and metastasis. Cancer cells have a higher dependency on molecular chaperones and are uniquely challenged due to imbalances caused by chromosomal abnormalities and overexpression of oncogenes, ultimately leading to cellular stress 7. As example, inhibitors of Heat Shock Protein 90 (HSP90) showed promising outcomes in the treatment of metastatic breast cancer 8. However, despite being in clinical trials since 1998, the success of HSP90 inhibitors in clinical trials remains mixed 9-11. Reasons such as dose-limiting toxicity, incomplete inhibition of HSP90, and insufficient downregulation of client proteins impeded the clinical use of current HSP90 inhibitors 12,13. In recent years,

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Molecular chaperone CCT3 supports proper mitotic progression and cell proliferation in hepatocellular carcinoma cells

Cited by 70 publications

References 38 publications

PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

Identification of the Key Genes and Pathways in Esophageal Carcinoma

Investigating Chaperonin-Containing TCP-1 subunit 2 as an essential component of the chaperonin complex for tumorigenesis

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