Nano-encapsulation of a novel anti-Ran-GTPase peptide for blockade of regulator of chromosome condensation 1 (RCC1) function in MDA-MB-231 breast cancer cells

Haggag, Yusuf A.; Matchett, Kyle B.; Dakir, El-Habib; Buchanan, Paul; Osman, Mohamed A.; El‐Gizawy, Sanaa A.; El‐Tanani, Mohamed; Faheem, Ahmed; McCarron, Paul A.

doi:10.1016/j.ijpharm.2017.02.006

Cited by 39 publications

(54 citation statements)

References 58 publications

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“…RAN has been shown to be implicated in carcinomas, such as breast cancer and lung cancer, by regulating cell adhesion, migration and invasion [31]. Several researches illustrated that RAN-inhibitory peptide-loaded PEG-PLGA NPs have great potential in curbing cancer through limiting the formation of active forms of RAN [32][33][34]. In addition, the expression level of RAN was significantly altered in glioblastoma, pancreatic cancer, neuroblastoma, melanoma [35][36][37][38][39][40].…”

Section: Discussionmentioning

confidence: 99%

The association of RAN and RANBP2 gene polymerphisms with Wilms tumor risk in Chinese children

Huang

Zhao

et al. 2020

J. Cancer

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Wilms tumor is considered to be the most common renal malignancy among children. RAN, a member of RAS superfamily, and its binding partner RANBP2 are related to the progression of multiple tumors. Nevertheless, the effects of the RAN and RANBP2 gene polymorphisms on the tumorigenesis of Wilms tumor remain unclarified. In this study, three potentially functional polymorphisms (rs56109543 C>T, rs7132224 A>G, and rs14035 C>T) in the RAN and one (rs2462788 C>T) in the RANBP2 were chosen to investigate their association with Wilms tumor susceptibility. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to assess the association of the selected polymorphisms with Wilms tumor susceptibility. Results shown that RAN rs7132224 AG/GG genotypes significantly increased Wilms tumor risk when compared to AA genotype (adjusted OR=1.40, 95% CI=1.01-1.95, P=0.047). Carriers of 1-3 risk genotypes have a significantly higher Wilms tumor risk than those without risk genotype (adjusted OR=1.49, 95% CI=1.07-2.07, P=0.020). Moreover, stratified analysis indicated that RAN rs56109543 CT/TT genotypes, RAN rs7132224 AG/GG genotypes and RANBP2 rs2462788 CT/TT genotypes remarkably increased Wilms tumor susceptibility among the subgroups. Our results indicated that RAN and RANBP2 polymorphisms were associated with Wilms tumor susceptibility in Chinese children. The role of RAN/RANBP2 in cancers deserves more attention.

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Section: Discussionmentioning

confidence: 99%

The association of RAN and RANBP2 gene polymerphisms with Wilms tumor risk in Chinese children

Huang

Zhao

et al. 2020

J. Cancer

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“…24 Selective advantage may explain why the RCC1 mutant allele is preferentially lost and why RCC1 rarely acquires somatic mutations in breast carcinomas. In fact, RCC1 blockage is being investigated as potential therapeutic means against aggressive breast tumors.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, RCC1 blockage is being investigated as potential therapeutic means against aggressive breast tumors. 24 Selective advantage may explain why the RCC1 mutant allele is preferentially lost and why RCC1 rarely acquires somatic mutations in breast carcinomas. It is possible that the loss of the c.1067_1086del19 mutant allele is a spurious observation, given the small number of tumor samples at hand.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing and case–control analyses identify RCC1 as a candidate breast cancer susceptibility gene

Riahi

Radmanesh

Schürmann

et al. 2018

Intl Journal of Cancer

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Breast cancer is a genetic disease but the known genes explain a minority of cases. To elucidate the molecular basis of breast cancer in the Tunisian population, we performed exome sequencing on six BRCA1/BRCA2 mutation-negative patients with familial breast cancer and identified a novel frameshift mutation in RCC1, encoding the Regulator of Chromosome Condensation 1. Subsequent genotyping detected the 19-bp deletion in additional 5 out of 153 (3%) breast cancer patients but in none of 400 female controls (p = 0.0015). The deletion was enriched in patients with a positive family history (5%, p = 0.0009) and co-segregated with breast cancer in the initial pedigree. The mutant allele was lost in 4/6 breast tumors from mutation carriers which may be consistent with the hypothesis that RCC1 dysfunction provides a selective disadvantage at the stage of tumor progression. In summary, we propose RCC1 as a likely breast cancer susceptibility gene in the Tunisian population.

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“…After success with our C-des design, we reason that similar mutations might exist naturally in human cancers, since activation of Ran is reported to be cell transforming and Ran overexpression is observed in different cancers 18,19,23,24,48 . Albeit relatively weak in level of activation, a high percentage of patient-derived Ran mutants tested are hyperactivated both in cells and in vitro demonstrated by immunoprecipitation or pull down.…”

Section: Ran Hyperactivation and Cellular Transformationmentioning

confidence: 99%

“…Further, Ran hyperactivation is associated with cellular transformation [18][19][20] and the progression of a few cancers [21][22][23] . Particularly, Ran is overexpressed in breast cancer and inhibition of Ran activation using anti-RCC1 peptide has demonstrated preferential cytotoxicity in breast cancer cells 24,25 .…”

mentioning

confidence: 99%

Destabilization of Ran C-terminus promotes GTP loading and occurs in multiple Ran cancer mutations

Zhang

Zhou

Tan

et al. 2018

Preprint

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Ran (Ras-related nuclear protein) plays several important roles in nucleo-cytoplasmic transport, mitotic spindle formation, nuclear envelope/nuclear pore complex assembly, and other diverse functions in the cytoplasm, as well as in cellular transformation when activated. Unlike other Ras superfamily proteins, Ran contains an auto-inhibitory C-terminal tail, which packs against its G domain and bias Ran towards binding GDP over GTP. The biological importance of this Cterminal tail is not well understood. By disrupting the interaction between the C-terminus and the G domain, we were able to generate Ran mutants that are innately active and potently bind to RanBP1 (Ran Binding Protein 1), nuclear export factor CRM1 and nuclear import factor KPNB1.In contrast to previously reported activated Ran mutants, the C-terminus destabilized mutants are hydrolysis competent in cells, support nuclear transport, and do not form nuclear rim staining. Crystal structures show that one of these C-terminal mutations slightly changes its mode of binding to RanBP1. Finally, a high percentage of Ran C-terminus mutations from cancer patients were found to be destabilizing and hyperactivating, suggesting that Ran Cdestabilization might be an unprecedented cellular transformation mechanism in affected cancers. This study also highlights a new drug design strategy towards treating patients with hyperactivated Ras proteins including K-Ras.

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Nano-encapsulation of a novel anti-Ran-GTPase peptide for blockade of regulator of chromosome condensation 1 (RCC1) function in MDA-MB-231 breast cancer cells

Cited by 39 publications

References 58 publications

The association of RAN and RANBP2 gene polymerphisms with Wilms tumor risk in Chinese children

The association of RAN and RANBP2 gene polymerphisms with Wilms tumor risk in Chinese children

Exome sequencing and case–control analyses identify RCC1 as a candidate breast cancer susceptibility gene

Destabilization of Ran C-terminus promotes GTP loading and occurs in multiple Ran cancer mutations

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