Aspirin-induced Bcl-2 translocation and its phosphorylation in the nucleus trigger apoptosis in breast cancer cells

Choi, Bo-Hwa; Chakraborty, Goutam; Baek, Kwanghee; Yoon, Ho Sup

doi:10.1038/emm.2013.91

Cited by 38 publications

(33 citation statements)

References 45 publications

(53 reference statements)

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“…Therefore, we observed the changes in levels of Bcl2, BAX, and cleaved caspase-3 in rat TSCs and determined that aspirin-induced apoptosis occurs through the mitochondrial/ caspase-3 pathway. Our results from this study are similar to those found in previous research [32][33][34][35]. We confirmed our results using an immunofluorescence assay in rat Achilles tendons.…”

Section: Discussionsupporting

confidence: 83%

High Concentration of Aspirin Induces Apoptosis in Rat Tendon Stem Cells via Inhibition of the Wnt/β-Catenin Pathway

Wang

Tang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in clinical practice to relieve fever and pain. Aspirin, as a representative NSAID, has been widely used in the treatment of tendinopathy. Some reports have demonstrated that aspirin can induce apoptosis in cancer cells. However, evidence regarding aspirin treatment for tendinopathy, especially the effect of this treatment on tendon stem cells (TSCs), is lacking. Understanding the effect of aspirin on tendinopathy may provide a basis for the rational use of NSAIDs in clinical practice. The aim of our study was to determine whether aspirin induces apoptosis in rat TSCs via the Wnt/β-catenin pathway. Methods: First, we used flow cytometry and fluorescence to detect TSC apoptosis. Protein expression of the apoptosis-related caspase-3 pathway was investigated via western blot analysis. Next, we used western blotting to determine the effect of aspirin on the Wnt/β-catenin pathway. We used immunostaining to detect the levels of Bcl2, cleaved caspase-3, and P-β-catenin in the Achilles tendon. Finally, we used flow cytometry, fluorescence, and western blotting to investigate the aspirin-induced apoptosis of TSCs via the Wnt/β-catenin pathway. Results: Aspirin induced morphological apoptosis in rat TSCs via the mitochondrial/caspase-3 pathway and induced cellular apoptosis in the Achilles tendon. Apoptosis was partly reversed after adding the Wnt signaling activator Wnt3a and lithium chloride (LiCl, a GSK-3β inhibitor). Aspirin administration led to a dose-dependent increase in COX-2 expression. Apoptosis was promoted after adding the COX-2 inhibitor NS398. Conclusion: The Wnt/β-catenin pathway plays a vital role in aspirin-induced apoptosis by regulating mitochondrial/caspase-3 function. Elevating COX-2 levels may protect cells against apoptosis. More importantly, the results remind us to consider the apoptotic effect of aspirin on TSCs and tendon cells when aspirin is administered to treat tendinopathy. The relationship between the positive and negative effects of aspirin remains a subject for future study.

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Section: Discussionsupporting

confidence: 83%

High Concentration of Aspirin Induces Apoptosis in Rat Tendon Stem Cells via Inhibition of the Wnt/β-Catenin Pathway

Wang

Tang

et al. 2018

Cell Physiol Biochem

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“…However, this is not the case as ASA was unable to regulate COX-2 expression at protein level in MDA-MB-231 cells (Supplementary Figure S4). Thus, consistent with previous work, [33][34][35] it appears that the BC cell death by ASA is mediated by apoptosis through the regulation of Bax/ Bcl2 and Caspase-3 system. Although the role of COX-2 signaling in this event is unclear, the involvement of this signaling pathway cannot be ruled out.…”

Section: Dose-dependent Inhibitory Effect Of Asa On Bc Cell Viabilitysupporting

confidence: 79%

“…51,52 The results of in vitro as well as animal studies also found an association between ASA use and growth inhibition of BC cells. 33,53,54 Ironically, the results from clinical and preclinical studies are inconsistent, 52,55 and thus a dilemma emerged about the role of ASA in prevention or delaying BC growth. Given the importance of this dilemma, we investigated the impact of ASA on different BC cell growth.…”

Section: Discussionmentioning

confidence: 99%

“…[33][34][35] However, minimum and incomplete information is available about the effect of ASA on human BC cell viability, growth, and differentiation. Thus, we initiated this study with the aim to determine the dosedependent effect of ASA on viability of estrogen receptor (ER)-positive BC cells and TNBC cells.…”

Section: Dose-dependent Inhibitory Effect Of Asa On Bc Cell Viabilitymentioning

confidence: 99%

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Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

Maity

Das

et al. 2015

Laboratory Investigation

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Acetylsalicylic acid (ASA), also known as aspirin, a classic, nonsteroidal, anti-inflammatory drug (NSAID), is widely used to relieve minor aches and pains and to reduce fever. Epidemiological studies and other experimental studies suggest that ASA use reduces the risk of different cancers including breast cancer (BC) and may be used as a chemopreventive agent against BC and other cancers. These studies have raised the tempting possibility that ASA could serve as a preventive medicine for BC. However, lack of in-depth knowledge of the mechanism of action of ASA reshapes the debate of risk and benefit of using ASA in prevention of BC. Our studies, using in vitro and in vivo tumor xenograft models, show a strong beneficial effect of ASA in the prevention of breast carcinogenesis. We find that ASA not only prevents breast tumor cell growth in vitro and tumor growth in nude mice xenograft model through the induction of apoptosis, but also significantly reduces the self-renewal capacity and growth of breast tumor-initiating cells (BTICs)/breast cancer stem cells (BCSCs) and delays the formation of a palpable tumor. Moreover, ASA regulates other pathophysiological events in breast carcinogenesis, such as reprogramming the mesenchymal to epithelial transition (MET) and delaying in vitro migration in BC cells. The tumor growth-inhibitory and reprogramming roles of ASA could be mediated through inhibition of TGF-β/ SMAD4 signaling pathway that is associated with growth, motility, invasion, and metastasis in advanced BCs. Collectively, ASA has a therapeutic or preventive potential by attacking possible target such as TGF-β in breast carcinogenesis.

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“…Meanwhile, PIK3CA is one of the most commonly mutated genes in estrogen receptor positive (ER+) human breast cancer with mutation frequencies of 45% in the luminal A subtype and 29% in the liminal B subtype [10]. Epidemiological [11] and experimental studies [12] both supported a role for aspirin in the treatment of ER+ breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Phospho-Aspirin-2 (MDC-22) Inhibits Estrogen Receptor Positive Breast Cancer Growth Both In Vitro and In Vivo by a Redox-Dependent Effect

et al. 2014

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Phospho-aspirin (PA-2) is a novel aspirin derivative that exhibits promising anticancer properties and is considerably safer than conventional aspirin. In this study, we investigated the chemotherapeutic efficacy of PA-2 in preclinical models of estrogen receptor positive (ER+) breast cancer and elucidated its mechanism of action. PA-2 inhibited the growth of ER+ cells more potently than aspirin in vitro, and exerted a triple cytokinetic effect that includes induction of apoptosis and cell cycle arrest as well as the inhibition of cell proliferation. PA-2 is highly efficacious in vivo, as treatment of established MCF7 xenografts with PA-2 induced tumor stasis (98.2% inhibition, p<0.01). PA-2 triggered the activation of p53-dependent apoptosis via two distinct mechanisms: 1) acetylation of p53 (at K373), which disrupts its interaction with its transcription repressor MDM2, and 2) translocation of p53 to the mitochondria leading to the dissipation of mitochondrial transmembrane potential (ΔΨm). Consistent with these observations, both the RNAi-mediated knockdown of p53 and forced deactylation via HDAC1 over-expression attenuated the anticancer effect of PA-2 in MCF7 cells. An upstream mediator of the signaling effects of PA-2 is RONS. PA-2 induced oxidative stress in vitro and in mice bearing MCF7 xenografts; its induction effect appears to be tumor-specific. Crucially, administration of N-acetylcysteine, a ROS scavenger, abrogated the effect of PA-2 on p53 acetylation and mitochondria translocation, thus identifying RONS as proximal molecules mediating the anticancer effect of PA-2. In summary, our findings demonstrate that PA-2 is a promising antineoplastic compound against ER+ breast cancer, warranting further evaluation as an anticancer agent.

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Aspirin-induced Bcl-2 translocation and its phosphorylation in the nucleus trigger apoptosis in breast cancer cells

Cited by 38 publications

References 45 publications

High Concentration of Aspirin Induces Apoptosis in Rat Tendon Stem Cells via Inhibition of the Wnt/β-Catenin Pathway

High Concentration of Aspirin Induces Apoptosis in Rat Tendon Stem Cells via Inhibition of the Wnt/β-Catenin Pathway

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

Phospho-Aspirin-2 (MDC-22) Inhibits Estrogen Receptor Positive Breast Cancer Growth Both In Vitro and In Vivo by a Redox-Dependent Effect

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