Polo-like kinase 3 inhibits glucose metabolism in colorectal cancer by targeting HSP90/STAT3/HK2 signaling

Ou, Baochi; Sun, Hongze; Zhao, Jingkun; Xu, Zhuoqing; Liu, Yuan; Feng, Hao; Peng, Zhihai

doi:10.1186/s13046-019-1418-2

Cited by 38 publications

(34 citation statements)

References 40 publications

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“…The inhibition of STAT3 could suppress the growth of glioma stem cells effectively combined with radiotherapy (27). Besides, it has been reported that STAT3 signaling pathway regulated the expression of HK-2 and PFKL (28,29). In the current study, we found that UBE2D3 knockdown inhibited STAT3 phosphorylation in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 51%

UBE2D3 Activates SHP-2 Ubiquitination to Promote Glycolysis and Proliferation of Glioma via Regulating STAT3 Signaling Pathway

Pan¹,

Bao²,

Zhang³

et al. 2021

Front. Oncol.

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Glioma is a primary brain cancer with high malignancy and morbidity. Current management for glioma cannot reach optimal remission. Therefore, it is necessary to find novel targets for glioma treatment. Ubiquitin-conjugating enzyme E2 D3 (UBE2D3) is involved in the pathogenesis of various kinds of cancer. However, its role in glioma remains unclear. Our study aims to explore the function and underlying mechanism of UBE2D3 in the development of glioma. By analysis with The Cancer Genome Atlas-Glioblastoma multiforme (TCGA-GBM) dataset, we found that UBE2D3 was highly expressed in glioma and it is positive correlation with glycolysis, apoptosis, and STAT3 pathway. Then, we explore the effects of UBE2D3 knockdown in the biological functions of glioma cell lines. Cell proliferation and apoptosis were estimated by cell counting kit-8 assay and flow cytometry. Extracellular acidification rate and oxygen consumption rate were estimated to determine the level of cell glycolysis. Xenograft experiments were performed to identify in vivo function of UBE2D3. The results showed that the inhibition of UBE2D3 could suppress the proliferation, glycolysis, and STAT3 phosphorylation of GBM both in vitro and in vivo. UBE2D3 could interact with SHP-2 and promoted its ubiquitination, which elevated the activation of STAT3 pathway. Overexpressed SHP-2 could reverse the effect of UBE2D3 and they shared contrary expression patterns in glioma and normal brain tissues. In summary, our study revealed that UBE2D3 could promote the ubiquitination of SHP-2, which activated STAT3 pathway and promoted glioma proliferation as well as glycolysis. UBE2D3 could be a potential target for glioma treatment.

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Section: Discussionsupporting

confidence: 51%

UBE2D3 Activates SHP-2 Ubiquitination to Promote Glycolysis and Proliferation of Glioma via Regulating STAT3 Signaling Pathway

Pan¹,

Bao²,

Zhang³

et al. 2021

Front. Oncol.

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“…Given the enrichment of PLK3 at the plasma membrane and Golgi apparatus, it will be interesting to test its potential impact on cell adhesion and intracellular trafficking that are regulated by PP6 phosphatase [48,49]. Finally, there is emerging evidence that expression of PLK3 could affect the therapeutical response in melanoma, prostate cancer and colon carcinoma [50][51][52]. Further phosphoproteomic studies are needed to identify new substrates of PLK3 that could explain its role in cell physiology and sensitivity to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Serine/threonine protein phosphatase 6 (PP6) is a heterotrimeric complex consisting of the catalytic subunit (PPP6C), SAPS domain-containing subunit (PPP6R1-3) and ankyrin repeat-domain containing regulatory subunit (ANKRD28, 44,52) [24]. PP6 was implicated in cell cycle progression, DNA damage repair, inflammatory signaling, and lymphocyte development [25].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of PLK3 Is Controlled by Protein Phosphatase 6

Perez

Palek

Morgen

et al. 2020

Cells

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Polo-like kinases play essential roles in cell cycle control and mitosis. In contrast to other members of this kinase family, PLK3 has been reported to be activated upon cellular stress including DNA damage, hypoxia and osmotic stress. Here we knocked out PLK3 in human non-transformed RPE cells using CRISPR/Cas9-mediated gene editing. Surprisingly, we find that loss of PLK3 does not impair stabilization of HIF1α after hypoxia, phosphorylation of the c-Jun after osmotic stress and dynamics of DNA damage response after exposure to ionizing radiation. Similarly, RNAi-mediated depletion of PLK3 did not impair stress response in human transformed cell lines. Exposure of cells to various forms of stress also did not affect kinase activity of purified EGFP-PLK3. We conclude that PLK3 is largely dispensable for stress response in human cells. Using mass spectrometry, we identify protein phosphatase 6 as a new interacting partner of PLK3. Polo box domain of PLK3 mediates the interaction with the PP6 complex. Finally, we find that PLK3 is phosphorylated at Thr219 in the T-loop and that PP6 constantly dephosphorylates this residue. However, in contrast to PLK1, phosphorylation of Thr219 does not upregulate enzymatic activity of PLK3, suggesting that activation of both kinases is regulated by distinct mechanisms.

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“…Multiple studies showed that STAT3 exerts a signi cant effect on the glycolysis and glucose-dependent addiction of tumor cells, which is known as the Warburg effect 16,17 . Speci cally, it has been reported that STAT3 regulates the glucose metabolism through increasing the HK2 expression in cancer cells 18 . Furthermore, STAT3 up-regulates LDHA expression to promote the proliferation of urinary bladder cancer cells 19 .…”

Section: Gsdmb Regulates the Glycolysis Via Activating Stat3 In Bladdmentioning

confidence: 99%

USP24-GSDMB complex promotes bladder cancer proliferation via activation of the STAT3 pathway

Zhang

Yan

et al. 2020

Preprint

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BackgroundBladder cancer is the fourth and tenth most common malignancy in men and women worldwide, respectively. One of the main reasons for the unsatisfactory therapeutic control of bladder cancer is that the molecular biological mechanism of bladder cancer is complex. Gasdermin B (GSDMB) is one member of the gasdermin family and participates in the regulation of cell pyroptosis. The role of GSDMB in bladder cancer has not been studied to date.MethodsThe clinical relevance of GSDMB was examined by the TCGA data set. Functional assays, such as the MTT assay, Celigo fluorescent cell-counting assay, Annexin V-APC assay and xenografts, were used to determine the biological role of GSDMB in bladder cancer. The interaction between GSDMB and STAT3, or GSDMB and USP24 were detected by Mass spectrometry and verified through immunoprecipitation. The relationship between USP24, GSDMB and STAT3 was examined by Western blot analysis and immunohistochemistry.ResultsIn this study, bioinformatics analysis indicated that the mRNA expression level of GSDMB in bladder cancer tissues was higher than that in adjacent normal tissues. Then, we showed that GSDMB promoted bladder cancer progression. Furthermore, we demonstrated that GSDMB interacted with STAT3 to increase the phosphorylation of STAT3 and modulate the glucose metabolism and promote tumor growth in bladder cancer cells. Besides, we also showed that USP24 stabilized GSDMB to activate STAT3 signaling, which was blocked by the USP24 inhibitor. ConclusionsWe suggested that aberrantly up-regulated GSDMB was responsible for enhancing the growth and invasion ability of bladder cancer cells. Then, we showed that GSDMB could bind to STAT3 and activate STAT3 signaling in bladder cancer. Furthermore, we also demonstrated that USP24 interacts with GSDMB and prevents GSDMB from degradation in bladder cancer cells. Therefore, the USP24/GSDMB/STAT3 axis may be a new targetable signaling pathway for bladder cancer treatment.

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Polo-like kinase 3 inhibits glucose metabolism in colorectal cancer by targeting HSP90/STAT3/HK2 signaling

Cited by 38 publications

References 40 publications

UBE2D3 Activates SHP-2 Ubiquitination to Promote Glycolysis and Proliferation of Glioma via Regulating STAT3 Signaling Pathway

UBE2D3 Activates SHP-2 Ubiquitination to Promote Glycolysis and Proliferation of Glioma via Regulating STAT3 Signaling Pathway

Phosphorylation of PLK3 Is Controlled by Protein Phosphatase 6

USP24-GSDMB complex promotes bladder cancer proliferation via activation of the STAT3 pathway

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