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Keywords = Perinucleolar compartment (PNC)

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17 pages, 3518 KB  
Review
Small Molecule with Big Impact: Metarrestin Targets the Perinucleolar Compartment in Cancer Metastasis
by Vivek K. Kashyap, Bhuvnesh P. Sharma, Divya Pandey, Ajay K. Singh, Godwin Peasah-Darkwah, Bhupesh Singh, Kuldeep K. Roy, Murali M. Yallapu and Subhash C. Chauhan
Cells 2024, 13(24), 2053; https://doi.org/10.3390/cells13242053 - 12 Dec 2024
Cited by 4 | Viewed by 3598
Abstract
Metarrestin (ML246) is a first-in-class pyrrole–pyrimidine-derived small molecule that selectively targets the perinucleolar compartment (PNC). PNC is a distinct subnuclear structure predominantly found in solid tumor cells. The occurrence of PNC demonstrates a positive correlation with malignancy, serving as an indicator of tumor [...] Read more.
Metarrestin (ML246) is a first-in-class pyrrole–pyrimidine-derived small molecule that selectively targets the perinucleolar compartment (PNC). PNC is a distinct subnuclear structure predominantly found in solid tumor cells. The occurrence of PNC demonstrates a positive correlation with malignancy, serving as an indicator of tumor aggressiveness, progression, and metastasis. Various promising preclinical results have led to the clinical translation of metarrestin into a first-in-human trial. This review aims to summarize (i) the current understanding of the structure and function of PNC and its role in cancer progression and metastasis, (ii) key findings from studies examining the effect of metarrestin on various cancers across the translational spectrum, including in vitro, in vivo, and human clinical trial studies, and (iii) the pharmaceutical relevance of metarrestin as a promising anticancer candidate. Furthermore, our molecular docking and MD simulation studies show that metarrestin binds to eEF1A1 and eEF1A2 with a strong and stable affinity and inhibits eEF1A2 more efficiently compared to eEF1A1. The promising results from preclinical studies suggest that metarrestin has the potential to revolutionize the treatment of cancer, heralding a paradigm shift in its therapeutic management. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets and Approaches, Genetic Markers and Signaling Pathways in Neoplasms)
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12 pages, 1704 KB  
Article
Perinucleolar Compartment (PNC) Prevalence as an Independent Prognostic Factor in Pediatric Ewing Sarcoma: A Multi-Institutional Study
by Elizabeth Gonzalez, Atif A. Ahmed, Laura McCarthy, Katherine Chastain, Sahibu Habeebu, Marta Zapata-Tarres, Rocio Cardenas-Cardos, Liliana Velasco-Hidalgo, Celso Corcuera-Delgado, Rodolfo Rodriguez-Jurado, Lilia García-Rodríguez, Alejandro Parrales, Tomoo Iwakuma, Midhat S. Farooqi, Brian Lee, Scott J. Weir and Terrie G. Flatt
Cancers 2023, 15(8), 2230; https://doi.org/10.3390/cancers15082230 - 10 Apr 2023
Cited by 2 | Viewed by 3544
Abstract
The perinucleolar compartment (PNC) is a small nuclear body that plays important role in tumorigenesis. PNC prevalence correlates with poor prognosis and cancer metastasis. Its expression in pediatric Ewing sarcoma (EWS) has not previously been documented. In this study, we analyzed 40 EWS [...] Read more.
The perinucleolar compartment (PNC) is a small nuclear body that plays important role in tumorigenesis. PNC prevalence correlates with poor prognosis and cancer metastasis. Its expression in pediatric Ewing sarcoma (EWS) has not previously been documented. In this study, we analyzed 40 EWS tumor cases from Caucasian and Hispanic patients for PNC prevalence by immunohistochemical detection of polypyrimidine tract binding protein and correlated the prevalence with dysregulated microRNA profiles. EWS cases showed staining ranging from 0 to 100%, which were categorized as diffuse (≥77%, n = 9, high PNC) or not diffuse (<77%, n = 31) for low PNC. High PNC prevalence was significantly higher in Hispanic patients from the US (n = 6, p = 0.017) and in patients who relapsed with metastatic disease (n = 4; p = 0.011). High PNC was associated with significantly shorter disease-free survival and early recurrence compared to those with low PNC. Using NanoString digital profiling, high PNC tumors revealed upregulation of eight and downregulation of 18 microRNAs. Of these, miR-320d and miR-29c-3p had the most significant differential expression in tumors with high PNC. In conclusion, this is the first study that demonstrates the presence of PNC in EWS, reflecting its utility as a predictive biomarker associated with tumor metastasis, specific microRNA profile, Hispanic ethnic origin, and poor prognosis. Full article
(This article belongs to the Special Issue Pediatric Cancer Biology: Basic and Translational Implications)
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