Silencing of Human Phosphatidylethanolamine-Binding Protein 4 Enhances Rituximab-Induced Death and Chemosensitization in B-Cell Lymphoma

Wang, Kai; Jiang, Yu; Zheng, Weiyan; Liu, Zhiyong; Li, Hui; Lou, Jianzhou; Gu, Meidi; Wang, Xiaojian

doi:10.1371/journal.pone.0056829

Cited by 14 publications

(9 citation statements)

References 43 publications

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“…It has been widely demonstrated that CAM-DR through direct cell contact and adhesion may be a major cause of tumor cell drug resistance in hematologic malignancies (23)(24)(25). The present study showed that adhesion to HS-5 cells or FN decreased CKIP-1 expression, and the depressed levels of CKIP-1 significantly promote the proliferation of NHL cells (Fig.…”

Section: Discussionsupporting

confidence: 58%

Silencing of CKIP-1 promotes tumor proliferation and cell adhesion-mediated drug resistance via regulating AKT activity in non-Hodgkins lymphoma

et al. 2016

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Casein kinase 2 interacting protein-1 (CKIP-1; also known as PLEKHO1) is involved in regulating many processes such as cell proliferation, differentiation and apoptosis. CKIP-1 also plays an important role in many types of cancer, such as colon, breast cancer and human osteosarcoma. In the present study, we found that CKIP-1 was reversely associated with the proliferation of non-Hodgkin's lymphoma (NHL) and cell adhesion mediated drug resistance (CAM-DR). We demonstrated that knockdown of CKIP-1 promoted the proliferation of NHL cells through interacting with Akt and suppressing Akt phosphorylation. In addition, adhesion of lymphoma cells to fibronectin or stroma cells (HS-5 cells) decreased CKIP-1 expression, which led to the upregulation of Akt phosphorylation. Importantly, we showed that the phosphorylation of Akt was correlated with CAM-DR phenotype in NHL cells. Taken together, the present study shed new light on the molecular mechanism of CAM-DR in NHL and targeting CKIP-1 may be a novel therapeutic target for NHL.

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Section: Discussionsupporting

confidence: 58%

Silencing of CKIP-1 promotes tumor proliferation and cell adhesion-mediated drug resistance via regulating AKT activity in non-Hodgkins lymphoma

et al. 2016

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“…Second, transfection of interference RNA for PEBP4 into cancer cells inhibits cell proliferation, migration and invasion or induces apoptosis, whereas overexpression of this protein causes opposite changes (17, 19, 23–26). Third, the expression levels of PEBP4 correlates with the sensitivity of cancer cells to chemotherapy or radiotherapy in which the upregulation of PEBP4 confers resistance to these therapies while its downregulation enhances the sensitivity (15, 26, 31, 32). These properties of PEBP4 are consistent with a role in promoting tumor transformation and progression, but are inconsistent with the inhibitory effect on the activation of the Raf-1/MEK/ERK pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly to PEBP1, PEBP4 was reported to associate with Raf-1 and MEK1, blocking MEK/ERK activation by TNFα or TRAIL and thereby inhibiting apoptosis (5, 15). PEBP4 is highly expressed in muscle, which leads to speculation of functional interactions between PEBP4 and Raff/MEK during myoblast differentiation (16).…”

Section: Introductionmentioning

confidence: 99%

Phosphatidylethanolamine binding protein 4 (PEBP4) is a secreted protein and has multiple functions

Liú

Lin

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Phosphatidylethanolamine binding proteins (PEBP) represent a superfamily of proteins that are conserved from bacteria to humans. In mammals, four members have been identified, PEBP1–4. To determine the functional differences among PEBP1–4 and the underlying mechanism for their actions, we performed a sequence alignment and found that PEBP4 contains a signal peptide and potential glycosylation sites, whereas PEBP1–3 are intracellular proteins. To test if PEBP4 is secreted, we made constructs with Myc epitope at the amino (N) terminus or carboxyl (C) terminus to mask the signal sequence or keep it free, respectively. Our data revealed that both mouse and human PEBP4 were secreted when the epitope was tagged at their C-terminus. To our surprise, secretion was dependent upon the C-terminal conserved domain in addition to the N-terminal signal sequence. When the epitope was placed to the N-terminus, the recombinant protein failed to secrete and instead, was retained in the cytoplasm. Mass spectrometry detected asparagine (N)-glycosylation on the secreted PEBP4. Although overexpression of N-terminal tagged PEBP4 resulted in an inhibition of ERK activation by EGF that with a C-terminal epitope tag did not have such an effect. Likewise, transfection of PEBP4 shRNA did not appear to affect ERK activation, suggesting that PEBP4 does not participate in the regulation of this pathway. In contrast, PEBP4 siRNA suppressed phosphorylation of Act at S473. Therefore, our results suggest that PEBP4 is a multifunctional protein and can be secreted. It will be important to investigate the mechanism by which PEBP4 is secreted and regulates cellular events.

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“…Recently, the prognosis of B-NHL patients has improved significantly due to better treatments, including the application of radiotherapy, chemotherapy and immunotherapy; however, factors such as tumor cell metastasis, drug resistance and relapse affect the prognosis of patients with B-NHL (22). It has been that several factors, such as miRNA (23), CHFR prophase checkpoint gene (24) and human phosphatidylethanolaminebinding protein 4 (25), may be associated with B-NHL occurrence and development, the molecular mechanisms of which require further study. Previous studies have reported that altered miRNA expression is associated with the development of lymphoma (26,27).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of microRNA-503 and reduced expression of kangai-1 in B-cell non-Hodgkin's lymphoma

Zhang

et al. 2016

Experimental and Therapeutic Medicine

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The aim of the present study was to determine the expression levels of microRNA-503 (miR-503) and the tumor suppressor gene, kangai-1 (KAI1), in B-cell non-Hodgkin's lymphoma (B-NHL). A total of 45 patients with B-NHL (including 29 cases with stage III/IV disease and 16 cases with stage I/II disease) were enrolled in this study. In addition, 26 patients with reactive lymphoid hyperplasia (RLH) were enrolled as the control patients. Reverse transcription-quantitative polymerase chain reaction was performed in order to measure the expression levels of miR-503 in B-NHL and RLH tissues, and to detect the expression levels of miR-503 and KAI1 in peripheral blood samples. In addition, KAI1 expression levels in B-NHL and RLH tissues were detected using western blotting and immunohistochemical analysis. The expression levels of miR-503 were found to be significantly increased in the tissues and peripheral blood of B-NHL patients when compared with those in RLH patients (P<0.05). However, KAI1 was strongly expressed in RLH tissues and weakly expressed in B-NHL tissues. Furthermore, the expression levels of KAI1 were significantly decreased in the tissues and peripheral blood of B-NHL patients when compared with those in the tissues and peripheral blood of RLH patients (P<0.05). The expression levels of miR-503 in the tissues and peripheral blood of patients with stage III/IV B-NHL were significantly higher compared with those with stage I/II B-NHL (P<0.05). By contrast, the expression levels of KAI1 in stage III/IV B-NHL tissues were significantly higher compared with those in stage I/II B-NHL tissues (P<0.05). In conclusion, miR-503 was highly expressed, whereas KAI1 was poorly expressed, in the tissues and peripheral blood of B-NHL patients. Thus, miR-503 may have an application as a novel therapeutic and diagnostic marker in B-NHL patients.

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Silencing of Human Phosphatidylethanolamine-Binding Protein 4 Enhances Rituximab-Induced Death and Chemosensitization in B-Cell Lymphoma

Cited by 14 publications

References 43 publications

Silencing of CKIP-1 promotes tumor proliferation and cell adhesion-mediated drug resistance via regulating AKT activity in non-Hodgkins lymphoma

Silencing of CKIP-1 promotes tumor proliferation and cell adhesion-mediated drug resistance via regulating AKT activity in non-Hodgkins lymphoma

Phosphatidylethanolamine binding protein 4 (PEBP4) is a secreted protein and has multiple functions

Increased expression of microRNA-503 and reduced expression of kangai-1 in B-cell non-Hodgkin's lymphoma

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