pRb2/p130 Localizes to the Cytoplasm in Diffuse Gastric Cancer

Cito, Letizia; Indovina, Paola; Forte, Iris Maria; Pentimalli, Francesca; Marzo, Domenico Di; Somma, Pasquale; Barone, Daniela; Penon, Antonella; Penon, Danila; Ceccherini, Elisa; Micheli, Pietro; Saragoni, Luca; Domenico, Marina Di; Feola, Antonia; Roviello, Franco; Mattioli, Eliseo; Giordano, Giovan Giacomo; Giordano, Antonio

doi:10.1002/jcp.24805

Cited by 10 publications

(11 citation statements)

References 31 publications

(36 reference statements)

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“…Hyperphosphorylation of RB can be due to increased cyclin levels, particularly cyclin D, which in complex with cyclin dependent kinase (CDK) 4/6 predominantly targets RB. Similar alterations in p107 and p130 are less common [ 11 ], but several studies, including ours, reported a mislocalization of p130 to the cytoplasm in some tumors [ 12 – 14 ].…”

Section: Introductionmentioning

confidence: 60%

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

et al. 2018

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Treatment options for high grade urothelial cancers are limited and have remained largely unchanged for several decades. Selinexor (KPT-330), a first in class small molecule that inhibits the nuclear export protein XPO1, has shown efficacy as a single agent treatment for numerous different malignancies, but its efficacy in limiting bladder malignancies has not been tested. In this study we assessed selinexor-dependent cytotoxicity in several bladder tumor cells and report that selinexor effectively reduced XPO1 expression and limited cell viability in a dose dependent manner. The decrease in cell viability was due to an induction of apoptosis and cell cycle arrest. These results were recapitulated in in vivo studies where selinexor decreased tumor growth. Tumors treated with selinexor expressed lower levels of XPO1, cyclin A, cyclin B, and CDK2 and increased levels of RB and CDK inhibitor p27, a result that is consistent with growth arrest. Cells expressing wildtype RB, a potent tumor suppressor that promotes growth arrest and apoptosis, were most susceptible to selinexor. Cell fractionation and immunofluorescence studies showed that selinexor treatment increased nuclear RB levels and mechanistic studies revealed that RB ablation curtailed the response to the drug. Conversely, limiting CDK4/6 dependent RB phosphorylation by palbociclib was additive with selinexor in reducing bladder tumor cell viability, confirming that RB activity has a role in the response to XPO1 inhibition. These results provide a rationale for XPO1 inhibition as a novel strategy for the treatment of bladder malignancies.

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Section: Introductionmentioning

confidence: 60%

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

et al. 2018

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“…RB1 belongs to a family of three proteins, including also retinoblastoma-like 1 (RBL1/p107) and retinoblastoma-like 2 (RBL2/p130) [ 7 ]. RBL2/p130 altered expression and delocalization was found in various cancers, in which it functions as a valuable prognostic marker [ 9 – 21 ]. Both RBL1/p107 and RBL2/p130 are involved in the negative regulation of cell cycle by interacting with E2F family members although in different combinations with respect to RB1 [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

RB1 dual role in proliferation and apoptosis: Cell fate control and implications for cancer therapy

et al. 2015

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Inactivation of the retinoblastoma (RB1) tumor suppressor is one of the most frequent and early recognized molecular hallmarks of cancer. RB1, although mainly studied for its role in the regulation of cell cycle, emerged as a key regulator of many biological processes. Among these, RB1 has been implicated in the regulation of apoptosis, the alteration of which underlies both cancer development and resistance to therapy. RB1 role in apoptosis, however, is still controversial because, depending on the context, the apoptotic cues, and its own status, RB1 can act either by inhibiting or promoting apoptosis. Moreover, the mechanisms whereby RB1 controls both proliferation and apoptosis in a coordinated manner are only now beginning to be unraveled. Here, by reviewing the main studies assessing the effect of RB1 status and modulation on these processes, we provide an overview of the possible underlying molecular mechanisms whereby RB1, and its family members, dictate cell fate in various contexts. We also describe the current antitumoral strategies aimed at the use of RB1 as predictive, prognostic and therapeutic target in cancer. A thorough understanding of RB1 function in controlling cell fate determination is crucial for a successful translation of RB1 status assessment in the clinical setting.

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“…Except for liver transplantation, there are no efficient antifibrotic treatments for end‐stage cirrhosis available; therefore, it is urgent to develop new therapies to stop or reverse fibrosis [Cohen‐Naftaly and Friedman, ]. Previous studies demonstrated that NS5ATP13 is involved in nucleologenesis and associated with several diseases, including H5N1 influenza [Zhu et al, ], hepatocellular carcinoma [Duan et al, ], gastric cancer [Cito et al, ], nasopharyngeal carcinoma [Hwang et al, ], and Alzheimer disease [Grupe et al, ]. Our DNA microarray and SSH data obtained by overexpressing NS5ATP13 in hepatocytes showed differential expression of liver fibrosis‐related genes [Dang et al, ; Zhang et al, ].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies concerning the role of NS5ATP13 in cell proliferation or apoptosis seem incongruous. pRb2/p130 cytoplasmic delocalization can lead to cell cycle deregulation, enhancing gastric tumorigenesis [Cito et al, ]. NS5ATP13 and TP53 synergistically activate the MDM2 promoter in NPC cells, contributing to NPC tumorigenesis [Hwang et al, ].…”

Section: Discussionmentioning

confidence: 99%

NS5ATP13 Promotes Liver Fibrogenesis Via Activation of Hepatic Stellate Cells

Liu

Han

et al. 2017

J. Cell. Biochem.

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Liver fibrosis is a reversible wound-healing response to any etiology of chronic hepatic injuries. Activation of hepatic stellate cells (HSCs) is the key event in liver fibrogenesis. Generally, persistent activation and proliferation of HSCs results in liver fibrosis progression, while primary mechanisms of liver fibrosis resolution are apoptosis and reversion to a quiescent phenotype of activated HSCs. NS5ATP13 (HCV NS5A-transactivated protein 13) is involved in nucleologenesis and tumorigenesis, but its role in liver fibrosis and HSC activation remains unclear. This study found that NS5ATP13 was upregulated in both fibrotic liver tissues and activated human HSCs induced by TGF-β1. Moreover, NS5ATP13 enhanced extracellular matrix (ECM) production and HSC activation, with or without TGF-β1 treatment, likely involving the TGF-β1/Smad3 signaling pathway. Additionally, NS5ATP13 boosted HSC proliferation by inhibiting cell apoptosis. Furthermore, HCV NS5A promoted the profibrogenic effect of NS5ATP13 partly through TGF-β1 and NF-κB p65 (RelA) upregulation. Meanwhile, NS5ATP13 was required for the pro-fibrogenic effect of NF-κB. Moreover, NS5ATP13 and NF-κB phosphorylation as well as HSC activation were reduced by CX-4945, a CK2 specific inhibitor. These findings indicated that NS5ATP13 acts as a profibrogenic factor, providing a potential target for antifibrotic therapies. J. Cell. Biochem. 118: 2463-2473, 2017. © 2017 Wiley Periodicals, Inc.

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pRb2/p130 Localizes to the Cytoplasm in Diffuse Gastric Cancer

Cited by 10 publications

References 31 publications

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

RB1 dual role in proliferation and apoptosis: Cell fate control and implications for cancer therapy

NS5ATP13 Promotes Liver Fibrogenesis Via Activation of Hepatic Stellate Cells

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