Phosphorylation of Nucleophosmin at Threonine 234/237 is associated with HCC metastasis

Ching, Rachel Hiu Ha; Lau, Eunice Y.; Ling, Patrick; Lee, Joyce Man Fong; Fai, Mark Kin; Cheng, Bowie Y.; Lo, Ronald; Ng, Irene Oi Lin; Lee, Terence

doi:10.18632/oncotarget.5820

Cited by 12 publications

(5 citation statements)

References 27 publications

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“…Interestingly, dephosphorylation of NPM/B23 has been shown to result in restoration of E2F1-dependent DNA repair [29]. Phosphorylation of the Thr234/237 sites in hepatocellular carcinoma cells was related to invasiveness and migration [30]. Phosphorylation of NPM/B23 at Thr199 is mediated by CDK2/cyclin E, with phospho-NPM/B23 (Thr199) being involved in both centrosome duplication and pre-mRNA processing [31].…”

Section: Discussionmentioning

confidence: 99%

Palbociclib Promotes Dephosphorylation of NPM/B23 at Threonine 199 and Inhibits Endometrial Cancer Cell Growth

Lin

Lee

Wang

et al. 2019

Cancers

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Endometrial cancer incidence rates are growing, especially in countries with rapid socioeconomic transitions. Despite recent advances in chemotherapy, hormone therapy, and targeted therapy, advanced/recurrent disease remains a clinical challenge. Palbociclib—a selective inhibitor of cyclin-dependent kinases (CDK) 4/6—has therapeutic potential against estrogen receptor (ER)-positive and HER2-negative breast cancer. However, the question as to whether it can be clinically useful in endometrial cancer remains open. Here, we show that combined treatment with palbociclib and megesterol acetate exerts synergistic antiproliferative effects against endometrial cancer cells. Treatment of cancer cells with palbociclib suppressed NPM/B23 phosphorylation at threonine 199 (Thr199). We further demonstrated that CDK6 acts as a NPM/B23 kinase. Palbociclib-induced NPM/B23 dephosphorylation sensitized endometrial cancer cells to megesterol acetate through the upregulation of ERα expression. Immunohistochemistry revealed an overexpression of phospho-NPM/B23 (Thr199) in human endometrial cancer, and phospho-NPM/B23 (Thr199) expression levels were inversely associated with Erα in clinical specimen. In a xenograft tumor model, the combination of palbociclib and megesterol acetate successfully inhibited tumor growth. Taken together, our data indicate that palbociclib promoted NPM/B23 dephosphorylation at Thr199—an effect mediated by disruption of CDK6 kinase activity. We conclude that palbociclib holds promise for the treatment of endometrial cancer when used in combination with megesterol acetate.

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Section: Discussionmentioning

confidence: 99%

Palbociclib Promotes Dephosphorylation of NPM/B23 at Threonine 199 and Inhibits Endometrial Cancer Cell Growth

Lin

Lee

Wang

et al. 2019

Cancers

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“…ATP binding cassette subfamily C member 1 ( 30 ), integrin subunit β1 (ITGB1) ( 31 , 32 ) and aldo-keto reductase family 1 member B ( 33 , 34 ) have been reported to be involved in chemoresistance/radioresistance and cancer metastasis. P21-activated kinase 2 ( 35 ), G protein nucleolar 3 ( 36 ), nucleophosmin ( 37 ) and pericentriolar material 1 ( 38 ) have been associated with metastatic characteristics in various types of cancer. These results indicate that different SP cells may have different molecular mechanisms for metastatic initiation, regulation, and evasion of conventional HCC chemotherapies.…”

Section: Resultsmentioning

confidence: 99%

Comparative proteomics of side population cells derived from human hepatocellular carcinoma cell lines with varying metastatic potentials

et al. 2018

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Metastasis and recurrence following surgery are major reasons for the high mortality rate and poor prognosis associated with hepatocellular carcinoma (HCC). Cancer stem cells (CSCs) are thought to be able to cause cancer, and to be the primary cause of tumor recurrence and metastasis. The underlying mechanisms of the metastatic potential of CSCs is poorly understood. In the present study, side population (SP) cells were isolated from 4 HCC cell lines, and their self-renewal and migratory abilities were compared. The results demonstrate that SP cells from different cell lines exhibited similar self-renewal abilities but different metastatic potentials. Furthermore, the overall proteomes of the SP cells were systematically quantified. This revealed 11 and 19 differentially expressed proteins (DEPs), upregulated and downregulated, respectively, associated with increased metastatic potential. These proteins were involved in the ‘regulation of mRNA processing’ and ‘cytoskeleton organization’ biological processes. The majority of the proteins were involved in ‘cell proliferation’, ‘migration’ and ‘invasion of cancer’, and may promote HCC metastasis in a synergistic manner. The AKT and nuclear factor-κB signaling pathways may contribute to the regulation of HCC metastasis through regulating the DEPs in SP cells. To the best of our knowledge, the present study is the first to demonstrate the overall proteome difference among SP cells from the different HCC cell lines with different metastatic potentials. The present study provides novel information regarding the metastatic potential of CSCs, which will facilitate further investigation of the topic.

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“…In brief, we rehydrated each insert by adding serum-free medium, replacing it with serum-free suspension with equal amounts of cells in the upper chamber, and incubating the cells for 12 to 24 hours to allow the cells to migrate toward/invade the lower chamber containing 10% FBS. After removing the non-invading cells in the upper chamber, the cells invading through the inserts were stained with the supplied dye, dissolved in extraction buffer, and transferred to 96-well plates for colorimetric reading at 560 nm by using ELISA microplate reader (GloMax Discover, Promega) [ 42 , 43 ].…”

Section: Methodsmentioning

confidence: 99%

Sulfatase-1 overexpression indicates poor prognosis in urothelial carcinoma of the urinary bladder and upper tract

et al. 2017

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Urothelial carcinoma (UC), arising from the urothelium of the urinary tract, can occur in the upper (UTUC) and the urinary bladder (UBUC). A representative molecular aberration for UC characteristics and prognosis remains unclear. Data mining of Gene Expression Omnibus focusing on UBUC, we identified sulfatase-1 (SULF1) upregulation is associated with UC progression. SULF1 controls the sulfation status of heparan sulfate proteoglycans and plays a role in tumor growth and metastasis, while its role is unexplored in UC. To first elucidate the clinical significance of SULF1 transcript expression, real-time quantitative RT-PCR was performed in a pilot study of 24 UTUC and 24 UBUC fresh samples. We identified that increased SULF1 transcript abundance was associated with higher primary tumor (pT) status. By testing SULF1 immunoexpression in independent UTUC and UBUC cohorts consisted of 340 and 295 cases, respectively, high SULF1 expression was significantly associated with advanced pT and nodal status, higher histological grade and presence of vascular invasion in both UTUC and UBUC. In multivariate survival analyses, high SULF1 expression was independently associated with worse DSS (UTUC hazard ratio [HR] = 3.574, P < 0.001; UBUC HR = 2.523, P = 0.011) and MeFS (UTUC HR = 3.233, P < 0.001; UBUC HR = 1.851, P = 0.021). Furthermore, depletion of SULF1 expression by using RNA interference leaded to impaired cell proliferative, migratory, and invasive abilities in vitro. In addition, we further confirmed oncogenic role of SULF1 with gain-of function experiments. In conclusion, our findings implicate the oncogenic role of SULF1 expression in UC, suggesting SULF1 as a prognostic and therapeutic target of UC.

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Phosphorylation of Nucleophosmin at Threonine 234/237 is associated with HCC metastasis

Cited by 12 publications

References 27 publications

Palbociclib Promotes Dephosphorylation of NPM/B23 at Threonine 199 and Inhibits Endometrial Cancer Cell Growth

Palbociclib Promotes Dephosphorylation of NPM/B23 at Threonine 199 and Inhibits Endometrial Cancer Cell Growth

Comparative proteomics of side population cells derived from human hepatocellular carcinoma cell lines with varying metastatic potentials

Sulfatase-1 overexpression indicates poor prognosis in urothelial carcinoma of the urinary bladder and upper tract

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