Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor

Chiu, Chang Fang; Chin, Hsien Kuo; Huang, Wei; Li, Bai; Huang, Hao; Weng, Jing Ru

doi:10.3390/biom9120824

Cited by 24 publications

(18 citation statements)

References 51 publications

(57 reference statements)

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“…Starvation-induced autophagy was associated with apoptosis in 28% of cells dually stained with AV/PI. The displacement of Bcl-2 from Beclin-1 and Bax, may be the driving force that triggered both autophagy and apoptosis [22]. In similar work, starved MDA MB-231 cells developed autophagy through the AMBRA1/mTOR pathway leading to an increase of LC3II, increase of autophagosomes but decrease of p62 protein [23].…”

Section: Discussionmentioning

confidence: 79%

β-Arrestin inhibition induces autophagy, apoptosis, G0/G1 cell cycle arrest in agonist-activated V2R receptor in breast cancer cells

et al. 2021

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Non-visual arrestins (β-arrestins) are endocytic proteins that mediate agonist activated GPCRs internalization and signaling pathways in an independent manner. The involvement of β-arrestins in cancer invasion and metastasis is increasingly reported. So, it is hypothesized that inhibition of β-arrstins may diminish the survival chances of cancer cells. This study aimed to evaluate the in vitro impact of inhibiting β-arrestins on the autophagic and/or apoptotic responsiveness of breast cancer cells.We used Barbadin to selectively inhibit β-Arr/AP2 interaction in AVP stimulated V2R receptor of triple negative breast cancer cells (MDA MB-231). Autophagy was assessed by the microtubule-associated protein 1 light chain 3-II (LC3II), apoptosis was measured by Annexin-V/PI staining and cell cycle distribution was investigated based upon the DNA content using ow cytometry. Barbadin reduced cell viability to 69.1% and increased the autophagy marker LC3 II and its autophagic effect disappeared in cells transiently starved in Earle's balanced salt solution (EBSS). Also, Barbadin mildly enhanced the expression of P62 mRNA and arrested 63.7% of cells in G0/G1 phase. In parallel, the drug induced apoptosis in 29.9% of cells (by AV/PI) and 27.8% of cells were trapped in sub-G1 phase. The apoptotic effect of Barbadin was enhanced when autophagy was inhibited by the PI3K inhibitor (Wortmannin).Conclusively, the data demonstrate the dual autophagic and apoptotic effects of β-βArr/AP2 inhibition in triple negative breast cancer cells. These observations nominate β-Arrs as selective targets in breast cancer treatment.Thus, this work was designed to explore the autophagic and apoptosis effects of the inhibition of β-Arr/AP2 interaction in hormonally stimulated breast cancer cells. Materials And MethodsKey Reagents: Barbadin (3-amino-5-(4-benzylphenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one) (Cat No. B118250), Arginine Vasopressin acetic acid salt (AVP) (Cat No. V991535) and Wortmannin (Cat No. W499400), were purchased from Toronto Research Chemicals, Toronto, Ontario, Canada). Trichostatin A (TSA) and dimethyl sulfoxide (DMSO) were from Sigma Chemicals, USA. Earle's balanced salt solution (EBSS) and other cell culture reagents (DMEM 4.5 g/L glucose with L glutamine, penicillin/streptomycin, fetal bovine serum (FBS) and Trypsin/EDTA) were from Lonza Pharma & Biotech. Cell culture and treatment MDA MB-231 cells [16] was generously provided by Department of Cancer Biology, NCI, Cairo University.Cells were cultured in Dulbecco's modi ed Eagle's Minimal Essential Medium (DMEM) supplemented with 10% heat inactivated FBS, 1% Penicillin/Streptomycin in a humidi ed atmosphere of 95% air and 5% CO 2 at 37 °C. Initially, cells were seeded with a low cell density then subcultured with particular densities in 100 mm, 6 wells, or 96 wells plates according to the experimental settings. Cell treatmentsAutophagy was induced by glucose oxygen deprivation, where cells were starved for 4 hours in EBSS, which does not contain nutrients nor growth factors, at...

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Section: Discussionmentioning

confidence: 79%

β-Arrestin inhibition induces autophagy, apoptosis, G0/G1 cell cycle arrest in agonist-activated V2R receptor in breast cancer cells

et al. 2021

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“…Another study showed that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) decreased HDAC7 protein levels in endometrial stromal sarcoma cells, producing an accumulation of autophagic vacuoles 41 . Recently, the HDAC8selective inhibitor HMC was shown to induce autophagy in MCF-7 cells 42 . In response to hypoxia in a myoblast cell line, class IIa HDAC9 was significantly increased, thereby inhibiting intracellular autophagy through direct binding to the promoter regions of Beclin 1, ATG7 and LC3 43 .…”

Section: Regulation Of Autophagy By P300-dependent Acetylationmentioning

confidence: 99%

Autophagy regulation by acetylation—implications for neurodegenerative diseases

et al. 2021

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Posttranslational modifications of proteins, such as acetylation, are essential for the regulation of diverse physiological processes, including metabolism, development and aging. Autophagy is an evolutionarily conserved catabolic process that involves the highly regulated sequestration of intracytoplasmic contents in double-membrane vesicles called autophagosomes, which are subsequently degraded after fusing with lysosomes. The roles and mechanisms of acetylation in autophagy control have emerged only in the last few years. In this review, we describe key molecular mechanisms by which previously identified acetyltransferases and deacetylases regulate autophagy. We highlight how p300 acetyltransferase controls mTORC1 activity to regulate autophagy under starvation and refeeding conditions in many cell types. Finally, we discuss how altered acetylation may impact various neurodegenerative diseases in which many of the causative proteins are autophagy substrates. These studies highlight some of the complexities that may need to be considered by anyone aiming to perturb acetylation under these conditions.

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“…Abnormal HDAC overexpression is observed in many tumors, such as colorectal cancer [ 12 ], breast cancer [ 13 ], and leukemia [ 14 ]. HDAC inhibitors (HDACis) are promising therapies for several types of cancer, such as breast cancer [ 15 ], colon cancer [ 16 ], hepatocellular carcinoma [ 17 ], and medulloblastoma [ 18 ], because they increase the susceptibility of tumor cells to apoptosis. HDACs can interact with p53 through deacetylation and reduce its transcriptional activity [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

NBM-BMX, an HDAC8 Inhibitor, Overcomes Temozolomide Resistance in Glioblastoma Multiforme by Downregulating the β-Catenin/c-Myc/SOX2 Pathway and Upregulating p53-Mediated MGMT Inhibition

Tsai

Chiou

et al. 2021

IJMS

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Although histone deacetylase 8 (HDAC8) plays a role in glioblastoma multiforme (GBM), whether its inhibition facilitates the treatment of temozolomide (TMZ)-resistant GBM (GBM-R) remains unclear. By assessing the gene expression profiles from short hairpin RNA of HDAC8 in the new version of Connectivity Map (CLUE) and cells treated by NBM-BMX (BMX)-, an HDAC8 inhibitor, data analysis reveals that the Wnt signaling pathway and apoptosis might be the underlying mechanisms in BMX-elicited treatment. This study evaluated the efficacy of cotreatment with BMX and TMZ in GBM-R cells. We observed that cotreatment with BMX and TMZ could overcome resistance in GBM-R cells and inhibit cell viability, markedly inhibit cell proliferation, and then induce cell cycle arrest and apoptosis. In addition, the expression level of β-catenin was reversed by proteasome inhibitor via the β-catenin/ GSK3β signaling pathway to reduce the expression level of c-Myc and cyclin D1 in GBM-R cells. BMX and TMZ cotreatment also upregulated WT-p53 mediated MGMT inhibition, thereby triggering the activation of caspase-3 and eventually leading to apoptosis in GBM-R cells. Moreover, BMX and TMZ attenuated the expression of CD133, CD44, and SOX2 in GBM-R cells. In conclusion, BMX overcomes TMZ resistance by enhancing TMZ-mediated cytotoxic effect by downregulating the β-catenin/c-Myc/SOX2 signaling pathway and upregulating WT-p53 mediated MGMT inhibition. These findings indicate a promising drug combination for precision personal treating of TMZ-resistant WT-p53 GBM cells.

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Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor

Cited by 24 publications

References 51 publications

β-Arrestin inhibition induces autophagy, apoptosis, G0/G1 cell cycle arrest in agonist-activated V2R receptor in breast cancer cells

β-Arrestin inhibition induces autophagy, apoptosis, G0/G1 cell cycle arrest in agonist-activated V2R receptor in breast cancer cells

Autophagy regulation by acetylation—implications for neurodegenerative diseases

NBM-BMX, an HDAC8 Inhibitor, Overcomes Temozolomide Resistance in Glioblastoma Multiforme by Downregulating the β-Catenin/c-Myc/SOX2 Pathway and Upregulating p53-Mediated MGMT Inhibition

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