APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC

Malfatti, Matilde Clarissa; Gerratana, Lorenzo; Dalla, Emiliano; Isola, Miriam; Damante, Giuseppe; Loreto, Carla Di; Puglisi, Fabio; Tell, Gianluca

doi:10.1186/s13046-019-1294-9

Cited by 33 publications

(30 citation statements)

References 98 publications

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“…APE1 is, consequently, wrongly delocalized within the cytoplasm in NPM1-mutated AML cells, leading to BER impairment and increased sensitivity to genotoxins [69]. Three bioactive compounds (spiclomazine, fiduxosin and SB206553), selected through high-throughput screening, inhibited NPM1-APE1 association and displayed antiproliferative activity in several cell lines [166,167].…”

Section: Synthetic Compoundsmentioning

confidence: 99%

Nucleophosmin in Its Interaction with Ligands

Cela

Matteo

Federici

2020

IJMS

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Nucleophosmin (NPM1) is a mainly nucleolar protein that shuttles between nucleoli, nucleoplasm and cytoplasm to fulfill its many functions. It is a chaperone of both nucleic acids and proteins and plays a role in cell cycle control, centrosome duplication, ribosome maturation and export, as well as the cellular response to a variety of stress stimuli. NPM1 is a hub protein in nucleoli where it contributes to nucleolar organization through heterotypic and homotypic interactions. Furthermore, several alterations, including overexpression, chromosomal translocations and mutations are present in solid and hematological cancers. Recently, novel germline mutations that cause dyskeratosis congenita have also been described. This review focuses on NPM1 interactions and inhibition. Indeed, the list of NPM1 binding partners is ever-growing and, in recent years, many studies contributed to clarifying the structural basis for NPM1 recognition of both nucleic acids and several proteins. Intriguingly, a number of natural and synthetic ligands that interfere with NPM1 interactions have also been reported. The possible role of NPM1 inhibitors in the treatment of multiple cancers and other pathologies is emerging as a new therapeutic strategy.

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Section: Synthetic Compoundsmentioning

confidence: 99%

Nucleophosmin in Its Interaction with Ligands

Cela

Matteo

Federici

2020

IJMS

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“…Moreover, APE1 protein expression quantification revealed higher levels in CDDP-resistant patients and was correlated with a lower OS and event-free interval (EFI). Recently, we have improved the knowledge of the role of APE1 and NPM1 in mediating the response of CDDP and carboplatin in TNBC cells lines, differing for APE1 and NPM1 protein expression [109]. As already demonstrated by Poletto et al [28], for other cell models, CDDP induced a shuttling of APE1 and NPM1 from nucleolus to nucleus compartments, which is possibly regulated to the non-DNA repair functions of APE1 on RNA metabolism.…”

Section: New Emerging Biomarkersmentioning

confidence: 99%

Platinum Salts in Patients with Breast Cancer: A Focus on Predictive Factors

Garutti

Pelizzari

Bartoletti

et al. 2019

IJMS

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Breast cancer (BC) is the most frequent oncologic cause of death among women and the improvement of its treatments is compelling. Platinum salts (e.g., carboplatin, cisplatin, and oxaliplatin) are old drugs still used to treat BC, especially the triple-negative subgroup. However, only a subset of patients see a concrete benefit from these drugs, raising the question of how to select them properly. Therefore, predictive biomarkers for platinum salts in BC still represent an unmet clinical need. Here, we review clinical and preclinical works in order to summarize the current evidence about predictive or putative platinum salt biomarkers in BC. The association between BRCA1/2 gene mutations and platinum sensitivity has been largely described. However, beyond the mutations of these two genes, several other proteins belonging to the homologous recombination pathways have been linked to platinum response, defining the concept of BRCAness. Several works, here reviewed, have tried to capture BRCAness through different strategies, such as homologous recombination deficiency (HRD) score and genetic signatures. Moreover, p53 and its family members (p63 and p73) might also be used as predictors of platinum response. Finally, we describe the mounting preclinical evidence regarding base excision repair deficiency as a possible new platinum biomarker.

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“…Although various anticancer therapeutic agents that can target specific receptors in breast cancer have been developed [ 8 ], TNBC does not respond to hormonal therapies that target HER2 and ER [ 9 ]. In order to overcome the limitations of TNBC therapeutic options, platinum-based compounds, including cisplatin and carboplatin, have been used in therapeutic trials for TNBC, in which they can effectively interfere with DNA replication and related cellular processes [ 10 , 11 , 12 , 13 ]. In addition to the development and application of novel anticancer agents, knowledge of specific TNBC characteristics will provide more options in the selection of therapeutic trials.…”

Section: Introductionmentioning

confidence: 99%

Potent Small-Molecule Inhibitors Targeting Acetylated Microtubules as Anticancer Agents Against Triple-Negative Breast Cancer

et al. 2020

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Microtubules are one of the major targets for anticancer drugs because of their role in cell proliferation and migration. However, as anticancer drugs targeting microtubules have side effects, including the death of normal cells, it is necessary to develop anticancer agents that can target microtubules by specifically acting on cancer cells only. In this study, we identified chemicals that can act as anticancer agents by specifically binding to acetylated microtubules, which are predominant in triple-negative breast cancer (TNBC). The chemical compounds disrupted acetylated microtubule lattices by interfering with microtubule access to alpha-tubulin acetyltransferase 1 (αTAT1), a major acetyltransferase of microtubules, resulting in the increased apoptotic cell death of MDA-MB-231 cells (a TNBC cell line) compared with other cells, such as MCF-10A and MCF-7, which lack microtubule acetylation. Moreover, mouse xenograft experiments showed that treatment with the chemical compounds markedly reduced tumor growth progression. Taken together, the newly identified chemical compounds can be selective for acetylated microtubules and act as potential therapeutic agents against microtubule acetylation enrichment in TNBC.

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APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC

Cited by 33 publications

References 98 publications

Nucleophosmin in Its Interaction with Ligands

Nucleophosmin in Its Interaction with Ligands

Platinum Salts in Patients with Breast Cancer: A Focus on Predictive Factors

Potent Small-Molecule Inhibitors Targeting Acetylated Microtubules as Anticancer Agents Against Triple-Negative Breast Cancer

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