Constitutive Activation of Caspase-3 and Poly ADP Ribose Polymerase Cleavage in Fanconi Anemia Cells

Lyakhovich, Alex; Surrallés, Jordi

doi:10.1158/1541-7786.mcr-09-0373

Cited by 30 publications

(27 citation statements)

References 46 publications

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“…The main known role of FA proteins is in the repair of DNA interstrand crosslinks . However, recent studies demonstrate that some other functions can be equally important, especially when dealing with cancer predisposition of FA patients . In this study we have reported for the first time elevated levels of IL‐8, MMP‐2, and MMP‐9 secretion by FAA, FAC cells and confirmed IL‐6 secretion described earlier for FA cells .…”

Section: Discussionsupporting

confidence: 88%

IL‐6, IL‐8, MMP‐2, MMP‐9 are overexpressed in Fanconi anemia cells through a NF‐κB/TNF‐α dependent mechanism

Epanchintsev

Pavithra

Verma

et al. 2014

Molecular Carcinogenesis

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Fanconi anemia (FA) is a rare autosomal recessive genetic disorder associated with a bone-marrow failure, genome instability, hypersensitivity to DNA crosslinking agents and a predisposition to cancer. Mutations have been documented in 16 FA genes that participate in the FA-BRCA DNA repair pathway, a fundamental pathway in the development of the disease and the presentation of its symptoms. FA cells have been characterized by an overproduction of cytokines, MAPKs, and Interleukins. Through this study we have identified the overexpression of additional secretory factors such as IL-6, IL-8, MMP-2, and MMP-9 in FA cells and in cells depleted of FANCA or FANCC and proved that their expression is under the control of NF-κB/TNF-α signaling pathways. We also demonstrated that these overexpressed secretory factors were effective in promoting the proliferation, migration, and invasion of surrounding tumor cells a fundamental event in the process of epithelial mesenchymal transition (EMT) and that they also modulated the expression of EMT markers such as E-cadherin and SNAIL. Overall our data suggest that the upregulation of EMT promoting factors in FA may contribute to predisposing FA patients to cancer, thereby providing new insights into possible therapeutic interventions.

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Section: Discussionsupporting

confidence: 88%

IL‐6, IL‐8, MMP‐2, MMP‐9 are overexpressed in Fanconi anemia cells through a NF‐κB/TNF‐α dependent mechanism

Epanchintsev

Pavithra

Verma

et al. 2014

Molecular Carcinogenesis

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“…A similar apoptotic response was not detected in EUFA423F cells at the concentrations and times tested, but those cells are an FA line. Cell death mechanisms in FA cells are less well-studied, and some cells constitutively produce caspase 3 and show PARP cleavage (46). Although we show evidence that the apoptotic response remains, this response might be different for BRCA lines that are not FA.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Synthetic Lethality via Combinations of ABT-888, a PARP Inhibitor, and Carboplatin In Vitro and In Vivo Using BRCA1 and BRCA2 Isogenic Models

Clark

Weitzel

O’Connor

2012

Molecular Cancer Therapeutics

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Individuals with an inherited BRCA1 or BRCA2 mutation have an elevated risk of developing breast cancer (BC). The resulting tumors typically lack homologous recombination repair, as do a subset of sporadic tumors with acquired BRCA deficiency. Clinical responses to monotherapy with platinum drugs or poly(ADP)ribose polymerase (PARP) inhibitors (PARPi) have been demonstrated for BRCA-associated cancers. However, there is limited data on combination therapy with PARPi and platinum drugs, the mechanism of action of this combination and the role of BRCA1 or BRCA2 in chemosensitivity. We compared the efficacy of ABT-888 (a PARPi) with that of cisplatin or carboplatin (platinum drugs) alone or in combinations by examining survival of treated Brca-proficient and -deficient mouse embryonic stem cells (mESC). In addition, drug-induced growth inhibition of a BRCA1 and a BRCA2 null cell line were compared to their isogenic BRCA-complemented lines. Whereas each monotherapy killed or inhibited proliferation of Brca/BRCA-deficient cells, an enhanced effect was observed after treatment with ABT-888 in combination with carboplatin. Moreover, the ABT-888/carboplatin combination delayed tumor growth in Brca2 xenografts. The drugs caused DNA damage, apoptosis and greater PARP activity in Brca/BRCA-deficient cells, and these effects correlated with increased chemosensitivity. Our data suggest that ABT-888 and carboplatin combination treatment will be more successful than monotherapy in addressing many BRCA-associated cancers. A randomized phase II trial has recently been initiated to test this hypothesis to assist in the discovery of more effective therapies for BRCA patients.

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“…This miR-34a damage-related effect could be particularly deleterious in FA patients because of the constitutive activation of caspase3, a key enzyme for apoptosis, identified in FA cells. 26 …”

Section: Discussionmentioning

confidence: 99%

Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia

Wang

Romero

Ratajczak

et al. 2012

Bone Marrow Transplant

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Fanconi anemia (FA) patients have an increased risk of acute GVHD (aGVHD) after hematopoietic SCT, with hypersensitivity to DNAcross-linking agents and defective DNA repair. MicroRNA-34 and p53 can induce apoptosis after DNA damage.Here we assessed epithelial cell apoptosis, and studied TP53 and miR-34a expression in the skin and gut biopsies in five non-transplanted FA patients, in 20 FA patients with aGVHD and in 25 acquired aplastic anemia patients (AA). Epithelial apoptosis was higher in FA than in acquired AA patients in both the skin and gut biopsies, though they had a similar preparative regimen. Further study on gut biopsies in FA patients showed that this deleterious effect was not linked to TP53 gene overexpression. As, among p53-independent signaling pathways of apoptosis, the microRNA-34 family mimics p53 apoptotic effects in response to DNA damage, we studied miR-34a expression in the same series of FA patients' gut biopsies. MiR-34a expression level was higher in severe aGVHD compared with non-aGVHD subjects or non-transplanted patients, and significantly related to apoptotic cell numbers across the three groups of FA patients. Thus, in FA patients, increased apoptosis occurs in target epithelial cells of severe aGVHD, and this deleterious effect is linked to overexpression of miR-34a but not TP53.

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Constitutive Activation of Caspase-3 and Poly ADP Ribose Polymerase Cleavage in Fanconi Anemia Cells

Cited by 30 publications

References 46 publications

IL‐6, IL‐8, MMP‐2, MMP‐9 are overexpressed in Fanconi anemia cells through a NF‐κB/TNF‐α dependent mechanism

IL‐6, IL‐8, MMP‐2, MMP‐9 are overexpressed in Fanconi anemia cells through a NF‐κB/TNF‐α dependent mechanism

Enhancement of Synthetic Lethality via Combinations of ABT-888, a PARP Inhibitor, and Carboplatin In Vitro and In Vivo Using BRCA1 and BRCA2 Isogenic Models

Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia

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