BRCA2 inhibition enhances cisplatin‐mediated alterations in tumor cell proliferation, metabolism, and metastasis

Rytelewski, Mateusz; Tong, Jessica; Buensuceso, Adrian; Leong, Hon S.; Vareki, Saman Maleki; Figueredo, René; Cresce, Christine Di; Wu, Sherry Y.; Herbrich, Shelley M.; Baggerly, Keith A.; Romanow, Larissa; Shepherd, Trevor G.; Deroo, Bonnie J.; Sood, Anil K.; Chambers, Ann F.; Vincent, Mark; Ferguson, Peter J.; Koropatnick, James

doi:10.1016/j.molonc.2014.05.017

Cited by 31 publications

(25 citation statements)

References 33 publications

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“…Recently, increasing studies have shown that activation of Aur A or inactivation/mutation of BRCA2 is associated with cancer metastasis [29–33]. In spite that different signal pathways have been reported, the tumor suppressor p53 may still play an important role in terms of the Aur A and BRCA2 status during cancer metastasis.…”

Section: Discussionmentioning

confidence: 99%

Fibrillin-1, induced by Aurora-A but inhibited by BRCA2, promotes ovarian cancer metastasis

et al. 2015

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While Aurora-A (Aur A) provokes, BRCA2 restrains primary tumorigenesis, the roles of Aur A and BRCA2 in cancer metastasis remains unclear. Here, we show that the metastatic promoting markers SLUG, FBN1, and MMP2, 9, 13 are either stimulated or suppressed by Aur A or BRCA2, but the metastatic suppressors E-cadherin, β-catenin, and p53 are either inhibited or promoted by Aur A or BRCA2, leading to enhanced or reduced cell migration and invasion. Further study suggests that FBN1 inhibits E-cadherin and β-catenin, but stimulates MMP2, 9, 13. Depletion of SLUG abrogates FBN1 and MMP9, but increases E-cadherin, while p53 decreases both SLUG and FBN1. Animal assays demonstrate that FBN1 promotes both ovarian tumorigenesis and metastasis. Clinically, overexpression of BRCA2 or Aur A in ovarian cancer tissues predicts good or poor overall and disease free survivals. High expression of SLUG or FBN1 indicates poor overall survivals, whereas high expression of FBN1 but not of SLUG predicts poor disease free survival. No significant associations between p53 expression and patient survivals were found. Overall, FBN1, acts at the downstream of Aur A and BRCA2, promotes ovarian cancer metastasis through the p53 and SLUG-associated signaling, which may be useful for ovarian cancer diagnosis and treatment.

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Section: Discussionmentioning

confidence: 99%

Fibrillin-1, induced by Aurora-A but inhibited by BRCA2, promotes ovarian cancer metastasis

et al. 2015

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“…To overcome these types of resistance, a second drug must be added to offset the mentioned drug-resistance mechanisms to drive cell death. For example, addition of BRCA2 antisense oligonucleotide which inhibited the DNA repair significantly enhanced the cytotoxicity of ciplatin to cancer cells [7]. Given this, combined treatment with other drugs is desirable to decrease the dose of cisplatin and overcome the cisplatin resistance.…”

Section: Introductionmentioning

confidence: 99%

Imperatorin acts as a cisplatin sensitizer via downregulating Mcl-1 expression in HCC chemotherapy

Cheng

et al. 2015

Tumor Biol.

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Acquisition of cisplatin resistance is the common and critical limitation for hepatocellular carcinoma (HCC) therapy. Our study was aimed to determine whether there were conditions under which the addition of imperatorin would reverse the resistance of HCC cells to cisplatin-based therapy. In this study, we found that addition of imperatorin significantly enhanced the cytotoxicity of cisplatin to HCC cells. Since the Mcl-1 was overexpressed in HCC cell lines (HepG2, HepG3B, PLC, Huh7) compared with normal liver cell line (L-O2), we found that the Mcl-1 expression was downregulated by imperatorin but not influenced by cisplatin in HCC cells. In addition, our results showed the combination of imperatorin and cisplatin induced apoptosis and ∆Ψm collapse more significantly compared with treatment of imperatorin or cisplatin alone. Furthermore, the imperatorin-induced sensitization for cisplatin-cytotoxicity to HCC cells was abolished by the transfection of Mcl-1 expression plasmid. Finally, we found that the addition of imperatorin significantly reversed the resistance to cisplatin in cisplatin-resistant HCC cells, which was Mcl-1 dependent. In summary, our study revealed that combination with imperatorin could enhance the antitumor activity of cisplatin via targeting Mcl-1 and reverse the resistance to cisplatin in HCC.

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“…The influence of possible ESE's on the cryptic splice site c.3550 and c.2398 should be further experimentally validated (Di Giacomo et al., ; Raponi et al., ). Knowledge on potentially activated splice sites in case of inactivation of the WT site, may be important to design adequate BRCA2 ASOs (antisense oligonucleotides), which have been proposed as a promising avenue to prevent resistance to PARP inhibitor therapy in several tumor types (Rytelewski et al., ) or as potential therapeutic anti‐cancer agent in combination with cisplatin (Rytelewski et al., ).…”

Section: Discussionmentioning

confidence: 99%

Thorough in silico and in vitro cDNA analysis of 21 putativeBRCA1andBRCA2splice variants and a complex tandem duplication inBRCA2allowing the identification of activated cryptic splice donor sites inBRCA2exon 11

et al. 2018

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For 21 putative BRCA1 and BRCA2 splice site variants, the concordance between mRNA analysis and predictions by in silico programs was evaluated. Aberrant splicing was confirmed for 12 alterations. In silico prediction tools were helpful to determine for which variants cDNA analysis is warranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implementation of these novel tools in clinical settings. Additionally, we report here for the first time activated cryptic donor sites in the large exon 11 of BRCA2 by evaluating the effect at the cDNA level of a novel tandem duplication (5' breakpoint in intron 4; 3' breakpoint in exon 11) and of a variant disrupting the splice donor site of exon 11 (c.6841+1G > C). Additional sites were predicted, but not activated. These sites warrant further research to increase our knowledge on cis and trans acting factors involved in the conservation of correct transcription of this large exon. This may contribute to adequate design of ASOs (antisense oligonucleotides), an emerging therapy to render cancer cells sensitive to PARP inhibitor and platinum therapies.

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BRCA2 inhibition enhances cisplatin‐mediated alterations in tumor cell proliferation, metabolism, and metastasis

Cited by 31 publications

References 33 publications

Fibrillin-1, induced by Aurora-A but inhibited by BRCA2, promotes ovarian cancer metastasis

Fibrillin-1, induced by Aurora-A but inhibited by BRCA2, promotes ovarian cancer metastasis

Imperatorin acts as a cisplatin sensitizer via downregulating Mcl-1 expression in HCC chemotherapy

Thorough in silico and in vitro cDNA analysis of 21 putativeBRCA1andBRCA2splice variants and a complex tandem duplication inBRCA2allowing the identification of activated cryptic splice donor sites inBRCA2exon 11

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