CENPH Inhibits Rapamycin Sensitivity by Regulating GOLPH3-dependent mTOR Signaling Pathway in Colorectal Cancer

Wu, Wei; Wu, Fan; Wang, Zaozao; Di, Jiabo; Yang, Jie; Gao, Pin; Jiang, Beihai; Su, Xiangqian

doi:10.7150/jca.19940

Cited by 20 publications

(22 citation statements)

References 39 publications

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“…Western blot was carried out as described [ 31 ]. The primary antibodies were used at the following dilutions: STK25 (1:1000, Cat #25821–1-AP, Proteintech), GOLPH3 (1:1000, Cat #19112–1-AP, Proteintech), PDHK1 (1:1000, Cat #3820, Cell Signaling Technology), HK2 (1:1000, Cat #2867, Cell Signaling Technology), LDHA (1:1000, Cat #2012, Cell Signaling Technology), AKT (1:1000, Cat #9272, Cell Signaling Technology), p-AKT (1:1000, Cat #9271, Cell Signaling Technology), mTOR Substrates Antibody Sampler Kit (1:1000, Cat #9862, Cell Signaling Technology), p70S6K (1:1000, Cat #2708, Cell Signaling Technology), p-p70S6K (1:200, Cat #9234, Cell Signaling Technology), and GOLPH3 (1:1000, Cat #19112–1-AP, Proteintech).…”

Section: Methodsmentioning

confidence: 99%

“…Human STK25 was inserted into the pET-28a(+) vector. The pGEX-4 T-1-GOLPH3 plasmid has been described [ 31 ]. His-STK25, GST-GOLPH3, and GST were expressed and purified in accordance with the manufacturer’s instructions (Amersham).…”

Section: Methodsmentioning

confidence: 99%

“…All statistical analyses were performed using SPSS 13.0 (SPSS Inc., Chicago, IL, USA). A two-sided P value of < 0.05 was considered to be statistically significant [ 31 ].…”

Section: Methodsmentioning

confidence: 99%

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STK25-induced inhibition of aerobic glycolysis via GOLPH3-mTOR pathway suppresses cell proliferation in colorectal cancer

Gao

et al. 2018

J Exp Clin Cancer Res

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BackgroundSerine/threonine protein kinase 25 (STK25) is critical in regulating whole-body glucose and insulin homeostasis and the accumulation of ectopic lipids. The Warburg effect, also known as aerobic glycolysis, is an essential metabolic characteristic of cancer cells. However, the effects of STK25 on aerobic glycolysis of cancer cells remain unexplored. The aim of this study is to investigate the role of STK25 in colorectal cancer (CRC) and to elucidate the underlying mechanisms.MethodsThe influences of STK25 on the cell proliferation were evaluated by MTT and colony formation assays. The roles of STK25 in aerobic glycolysis were determined by glucose uptake and lactate production assays. The interaction between STK25 and GOLPH3 was detected by co-immunoprecipitation, GST pull-down, and His-tag pull-down assays. Western blot was used to measure the expression of glycolytic genes, and the status of kinases in mTOR pathway. Moreover, a xenograft mouse model was used to investigate the effects of STK25 in vivo. The prognostic significance of STK25 was analyzed using public CRC datasets by a log-rank test.ResultsSTK25 suppressed proliferation, glycolysis and glycolytic gene expression in CRC cells. STK25 interacted with GOLPH3 and mediated glycolysis through GOLPH3-regulated mTOR signaling. Consistent with these observations, silencing of STK25 promoted tumor growth and glycolytic gene expression in an in vivo xenograft mouse model. Moreover, high levels of STK25 correlated with favorable prognosis in patients with CRC.ConclusionsOur results demonstrated that STK25 negatively regulates the proliferation and glycolysis via GOLPH3-dependent mTOR signaling. Accordingly, STK25 could be a potential therapeutic target for the treatment of CRC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0808-1) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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STK25-induced inhibition of aerobic glycolysis via GOLPH3-mTOR pathway suppresses cell proliferation in colorectal cancer

Gao

et al. 2018

J Exp Clin Cancer Res

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“…Centromere protein H (CENP-H) is a component of the kinetochore and plays an essential role in mitotic processes (Lu et al 2017), accurate chromosome segregation (Zhu et al 2015) as well as appropriate kinetochore assembly (Zhao et al 2012). Many studies have shown that CENPH is closely associated with human cancers, including colorectal cancer (Wu et al 2017), renal cell carcinoma (Wu et al 2015), non-small cell lung cancer (Liao et al 2009) as well as breast cancer (Walian et al 2016). However, there is no current evidence on the correlation PeerJ reviewing PDF | (2020:05:49377:1:1:NEW 16 Aug 2020)…”

Section: Manuscript To Be Reviewedmentioning

confidence: 99%

Peer Review #2 of "Identification of NUF2 and FAM83D as potential biomarkers in triple-negative breast cancer (v0.2)"

2020

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Background. Breast cancer is a heterogeneous disease. Compared with other subtypes of breast cancer, triple-negative breast cancer (TNBC) is easy to metastasize and has a short survival time, less choice of treatment options. Here, we aimed to identify the potential biomarkers to TNBC diagnosis and prognosis. Material/Methods. Three independent data sets (GSE45827, GSE38959, GSE65194) were downloaded from the Gene Expression Omnibus (GEO). The R software packages were used to integrate the gene profiles and identify differentially expressed genes (DEGs). A variety of bioinformatics tools were used to explore the hub genes, including the DAVID database, STRING database and Cytoscape software. Reverse transcription quantitative PCR (RT-qPCR) was used to verify the hub genes in 14 pairs of TNBC paired tissues. Results. In this study, we screened out 161 DEGs between 222 non-TNBC and 126 TNBC samples, of which 105 genes were up-regulated and 56 were down-regulated. These DEGs were enriched for 27 GO terms and 2 pathways. GO analysis enriched mainly in "cell division", "chromosome, centromeric region" and "microtubule motor activity". KEGG pathway analysis enriched mostly in "Cell cycle" and "Oocyte meiosis". PPI network was constructed and then 10 top hub genes were screened. According to the analysis results of the Kaplan-M eier survival curve, the expression levels of only NUF2, FAM83D and CENPH were associated with the recurrence-free survival in TNBC samples (P<0.05). RT-qPCR confirmed that the expression levels of NUF2 and FAM83D in TNBC tissues were indeed up-regulated significantly. Conclusions. The comprehensive analysis showed that NUF2 and FAM83D could be used as potential biomarkers for diagnosis and prognosis of TNBC.

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“…When GOLPH3 was first identified as an oncogene, it was observed to be able to drive increased growth factor signaling (47). Numerous studies have corroborated the ability of GOLPH3 to drive increased growth factor signaling, although the mechanism remains uncertain (71)(72)(73)(74). Certainly, increasing growth factor signaling is a mechanism to promote oncogenic transformation.…”

Section: Mechanisms Of Oncogenesis By the Golph3 Complexmentioning

confidence: 99%

GOLPH3: a Golgi phosphatidylinositol(4)phosphate effector that directs vesicle trafficking and drives cancer

Kuna

Field

2019

Journal of Lipid Research

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ROLE OF THE PTDINS(4)P/GOLPH3 COMPLEX IN GOLGI FORWARD TRAFFICKING GOLPH3 (also known as GMx33 and GPP34) was first discovered by proteomic studies of purified Golgi fractions (6, 7). Further investigation revealed GOLPH3 to be a peripheral membrane protein, highly localized to the trans-Golgi and to vesicles budding from the trans-Golgi (6-8). The yeast ortholog of GOLPH3, VPS74, was also found to function at the Golgi (9, 10). However, the mechanism of localization to the Golgi and the purpose of GOLPH3 at the Golgi remained uncertain. During a genome-wide, proteomic screen for phosphoinositide binding proteins, we identified GOLPH3 as a protein that binds tightly and specifically to PtdIns(4)P (see Fig. 1) (11). We found that GOLPH3 binding to PtdIns(4)P is responsible for its localization to the Golgi in yeast and mammalian cells (11). GOLPH3 is a highly abundant (10 6 molecules per cell), ubiquitously expressed protein (11, 12). Thus, it is a major effector of PtdIns(4)P at the Golgi. PtdIns(4)P was already well known to be highly enriched at the trans-Golgi (13-15). From yeast to humans, PtdIns(4) P at the Golgi is required for Golgi-to-plasma membrane trafficking (16-19). Certainly, many effectors of PtdIns(4) P besides GOLPH3 have been described. These have a variety of activities, including several that function as nonvesicular lipid transporters, and have been the subject of many previous reviews (20-22). Two phosphatidylinositol-4-kinases (PI-4-kinases), PI4KII and PI4KIII, localize to the Golgi to produce PtdIns(4)P (13, 14, 23). Currently, we lack a detailed understanding of the differential roles for Abstract GOLPH3 is a peripheral membrane protein localized to the Golgi and its vesicles, but its purpose had been unclear. We found that GOLPH3 binds specifically to the phosphoinositide phosphatidylinositol(4)phosphate [PtdIns(4) P], which functions at the Golgi to promote vesicle exit for trafficking to the plasma membrane. PtdIns(4)P is enriched at the trans-Golgi and so recruits GOLPH3. Here, a GOLPH3 complex is formed when it binds to myosin18A (MYO18A), which binds F-actin. This complex generates a pulling force to extract vesicles from the Golgi; interference with this GOLPH3 complex results in dramatically reduced vesicle trafficking. The GOLPH3 complex has been identified as a driver of cancer in humans, likely through multiple mechanisms that activate secretory trafficking. In this review, we summarize the literature that identifies the nature of the GOLPH3 complex and its role in cancer. We also consider the GOLPH3 complex as a hub with the potential to reveal regulation of the Golgi and suggest the possibility of GOLPH3 complex inhibition as a therapeutic approach in cancer.-Kuna, R. S., and S. J. Field. GOLPH3: a Golgi phosphatidylinositol(4)phosphate effector that directs vesicle trafficking and drives cancer.

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CENPH Inhibits Rapamycin Sensitivity by Regulating GOLPH3-dependent mTOR Signaling Pathway in Colorectal Cancer

Cited by 20 publications

References 39 publications

STK25-induced inhibition of aerobic glycolysis via GOLPH3-mTOR pathway suppresses cell proliferation in colorectal cancer

STK25-induced inhibition of aerobic glycolysis via GOLPH3-mTOR pathway suppresses cell proliferation in colorectal cancer

Peer Review #2 of "Identification of NUF2 and FAM83D as potential biomarkers in triple-negative breast cancer (v0.2)"

GOLPH3: a Golgi phosphatidylinositol(4)phosphate effector that directs vesicle trafficking and drives cancer

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