Profilin potentiates chemotherapeutic agents mediated cell death via suppression of NF-κB and upregulation of p53

Zaidi, Syed; Raviprakash, Nune; Mokhamatam, Raveendra B.; Gupta, Pankaj; Manna, Sunil K.

doi:10.1007/s10495-016-1222-9

Cited by 16 publications

(20 citation statements)

References 29 publications

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“…Profilin 1 plays a double role in the regulation of osteoclast differentiation. On one hand, it directly suppresses NF‐κB activity, a key molecule for osteoclast formation and survival . In addition, PFN1 directly interacts with and prevents the degradation of the phosphatase PTEN, known to negatively regulate osteoclast differentiation .…”

Section: Resultsmentioning

confidence: 99%

The Loss of Profilin 1 Causes Early Onset Paget's Disease of Bone

Carlo

Pazzaglia

Esposito

et al. 2020

Journal of Bone and Mineral Research

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Paget's disease of bone (PDB) is a late-onset disorder frequently caused by mutations in the SQSTM1 gene, leading to hyperactive osteoclasts and resulting in bone pain, deformities, and fractures. However, some more severe forms of PDB-negative for SQSTM1 mutations-have been described, in which the disease degenerates into bone cancers and shows a poor prognosis. Osteosarcoma is the most frequent and aggressive tumor arising in PDB (OS/PDB), with a 5-year survival rate almost nil, but the underlying molecular mechanism is unknown. Here, we investigated an extended pedigree with 11 individuals affected by early onset and polyostotic PDB, mainly interesting the appendicular skeleton. Interestingly, three members also developed secondary osteosarcoma. We performed exome sequencing and identified a 4-bp deletion in the PFN1 gene, resulting in the degradation of the mutant protein. Copy number screening on 218 PDB individuals of our biobank disclosed that four of them (~2%) carry a germline heterozygous deletion of PFN1. The identification of these subjects, who exhibit a particularly severe form of disease, emphasizes the diagnostic value of this genetic screening to identify PDB individuals predisposed to develop osteosarcoma. In fact, we detected allelic imbalance at PFN1 locus also in 8 of 14 (57%) sporadic OS/PDB, further proving its causative role. in vitro experiments also confirmed PFN1 involvement in this form of PDB. Indeed, CRISPR-Cas9-mediated Pfn1 knockout in pre-osteoclasts resulted into enhanced osteoclast differentiation and resorption, with the formation of large osteoclasts never described before in PDB. In addition, Pfn1 lacking pre-osteoblasts lost their differentiation capability and failed to efficiently mineralize bone. Moreover, they acquired features of malignant transformation, including loss of focal adhesions and increased invasion ability. In conclusion, these findings disclose PFN1 haploinsufficiency as the pathological mechanism in OS/PDB.

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Section: Resultsmentioning

confidence: 99%

The Loss of Profilin 1 Causes Early Onset Paget's Disease of Bone

Carlo

Pazzaglia

Esposito

et al. 2020

Journal of Bone and Mineral Research

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“…Inhibiting the NF-κB pathway enhances the antitumor effect of cabazitaxel by downregulating Bcl-2 in pancreatic cancer ZEQUN LI [1][2][3][4] , ZEFENG XUAN [1][2][3][4] , JIAN CHEN [1][2][3][4] , WENFENG SONG [1][2][3][4] , SHIYU ZHANG [1][2][3][4] , CHENG JIN [1][2][3][4] , MENGQIAO ZHOU [1][2][3][4] , SHUSEN ZHENG [1][2][3][4] and PENGHONG SONG [1][2][3][4] gene (14,15). Furthermore, the downregulation or inhibition of NF-κB activation is an effective treatment option for certain types of cancer, including colorectal cancer, glioblastoma, breast cancer and lung cancer (16,17). It has been reported that NF-κB p65 directly bound to NME5 serves a central role in PC chemoresistance by inhibiting gemcitabine-induced apoptosis and G1 phase arrest (18).…”

Section: Introductionmentioning

confidence: 99%

Inhibiting the NF-κB pathway enhances the antitumor effect of cabazitaxel by downregulating Bcl-2 in pancreatic cancer

Xuan

Chen

et al. 2020

Int J Oncol

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Optimizing the currently available treatment options for pancreatic cancer (PC) is a priority. Cabazitaxel (CTX), a semisynthetic taxane, is mainly used for treating patients with PC who are resistant to paclitaxel (PTX) or docetaxel, due its poor affinity for P-glycoprotein. However, there are only a few studies demonstrating the effect of CTX on PC. The present study aimed to investigate the efficiency and underlying mechanism of CTX in PC treatment. Cell proliferation, colony formation assay and apoptosis analysis were achieved in the two human PC cell lines AsPC-1 and BxPC-3. Drug sensitivity test was performed in BxPC-3 tumor-bearing mice. The results demonstrated that CTX had a lower half maximal inhibitory concentration compared with PTX for the inhibition of cell proliferation, both in vivo and in vitro. Furthermore, the nuclear factor-κB (NF-κB) pathway was activated following cell treatment with CTX, and NF-κB p65 overexpression attenuated CTX cytotoxicity. In addition, the combined use of the specific NF-κB inhibitor caffeic acid phenethyl ester (CAPE) with CTX significantly enhanced CTX effect, both in vivo and in vitro. Similarly, the mRNA and protein expression of B-cell lymphoma-2 was decreased in AsPC-1 and BxPC-3 cells following treatment with CTX and CAPE, suggesting that NF-κB may serve a crucial role in CTX efficiency. In conclusion, results from our previous study indicated that CTX could potentially replace PTX in the treatment of PC, and the present study demonstrated that CTX combination with an NF-κB inhibitor may be considered as a potential therapeutic option for PC, which may improve the prognosis of patients with PC.

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“…Low expressions of CAP‐G, HSP27 and L‐plastin were reported in vincristine‐resistant ALL (Verrills et al , , ) and a low expression of HSP27 was observed in doxorubicin‐resistant uterine cancer cells (May et al , ). Moreover, the high expression of myosin‐9 sensitized acute myeloid leukaemia cells to apoptosis by the alkaloid homoharringtonine (Zhang et al , ) and Profilin‐1 potentiated several chemotherapeutic agents (including doxorubicin) to mediate cell death via the suppression of NF‐κB and upregulation of p53 (Zaidi et al , ). However, some actin‐related proteins in our study were reported to correlate with poor prognosis in other cancers, including S100‐A11, cofilin‐1, fibrillin‐1 and Rap‐1b.…”

Section: Discussionmentioning

confidence: 99%

Expression of ribosomal and actin network proteins and immunochemotherapy resistance in diffuse large B cell lymphoma patients

et al. 2018

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Diffuse large B cell lymphoma (DLBCL) patients with early relapse or refractory disease have a very poor outcome. Immunochemotherapy resistance will probably, also in the era of targeted drugs, remain the major cause of treatment failure. We used proteomic mass spectrometry to analyse the global protein expression of micro-dissected formalin-fixed paraffin-embedded tumour tissues from 97 DLBCL patients: 44 with primary refractory disease or relapse within 1 year from diagnosis (REF/REL), and 53 who were progression-free more than 5 years after diagnosis (CURED). We identified 2127 proteins: 442 were found in all patients and 102 were differentially expressed. Sixty-five proteins were overexpressed in REF/REL patients, of which 46 were ribosomal proteins (RPs) compared with 2 of the 37 overexpressed proteins in CURED patients (P = 7·6 × 10 ). Twenty of 37 overexpressed proteins in CURED patients were associated with actin regulation, compared with 1 of 65 in REF/REL patients (P = 1·4 × 10 ). Immunohistochemical staining showed higher expression of RPS5 and RPL17 in REF/REL patients while MARCKS-like protein, belonging to the actin network, was more highly expressed in CURED patients. Even though functional studies aimed at individual proteins and protein interactions to evaluate potential clinical effect are needed, our findings suggest new mechanisms behind immunochemotherapy resistance in DLBCL.

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Profilin potentiates chemotherapeutic agents mediated cell death via suppression of NF-κB and upregulation of p53

Cited by 16 publications

References 29 publications

The Loss of Profilin 1 Causes Early Onset Paget's Disease of Bone

The Loss of Profilin 1 Causes Early Onset Paget's Disease of Bone

Inhibiting the NF-κB pathway enhances the antitumor effect of cabazitaxel by downregulating Bcl-2 in pancreatic cancer

Expression of ribosomal and actin network proteins and immunochemotherapy resistance in diffuse large B cell lymphoma patients

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