A new synthetic HDAC inhibitor, MHY218, induces apoptosis or autophagy-related cell death in tamoxifen-resistant MCF-7 breast cancer cells

Gene expression is often altered by epigenetic modifications that can significantly influence the growth ability and progression of cancers. SAHA (Suberoylanilide hydroxamic acid, also known as Vorinostat), a well-known Histone deacetylase (HDAC) inhibitor, can stop cancer growth and metastatic processes through epigenetic alterations. On the other hand, Letrozole is an aromatase inhibitor that can elicit strong anti-cancer effects on breast cancer through direct and indirect mechanisms. A newly developed inhibitor, RG7388 specific for an oncogene-derived protein called MDM2, is in clinical trials for the treatment of various cancers. In this paper, we performed assays to measure the effects of cell cycle arrest resulting from individual drug treatments or combination treatments with SAHA + letrozole and SAHA + RG7388, using the MCF-7 breast cancer cells. When SAHA was used individually, or in combination treatments with RG7388, a significant increase in the cytotoxic effect was obtained. Induction of cell cycle arrest by SAHA in cancer cells was evidenced by elevated p21 protein levels. In addition, SAHA treatment in MCF-7 cells showed significant up-regulation in phospho-RIP3 and MLKL levels. Our results confirmed that cell death caused by SAHA treatment was primarily through the induction of necroptosis. On the other hand, the RG7388 treatment was able to induce apoptosis by elevating BAX levels. It appears that, during combination treatments, with SAHA and RG7388, two parallel pathways might be induced simultaneously, that could lead to increased cancer cell death. SAHA appears to induce cell necroptosis in a p21-dependent manner, and RG7388 seems to induce apoptosis in a p21-independent manner, outlining differential mechanisms of cell death induction. However, further studies are needed to fully understand the intracellular mechanisms that are triggered by these two anti-cancer agents.

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Doxorubicin resistance mediated by cytoplasmic macrophage colony-stimulating factor is associated with switch from apoptosis to autophagic cell death in MCF-7 breast cancer cells

Experimental Biology and Medicine ◽

10.1177/1535370216660399 ◽

2016 ◽

Vol 241 (18) ◽

pp. 2086-2093 ◽

Cited By ~ 5

Author(s):

Mengxia Zhang ◽

Hailiang Zhang ◽

Fan Tang ◽

Yuhua Wang ◽

Zhongcheng Mo ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Colony Stimulating Factor ◽

Doxorubicin Resistance ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor ◽

Mcf 7

Macrophage colony-stimulating factor is a vital factor in maintaining the biological function of monocyte–macrophage lineage. It is expressed in many tumor tissues and cancer cells. Recent findings indicate that macrophage colony-stimulating factor might contribute to chemoresistance, but the precise mechanisms are unclear. This study was to explore the effect of macrophage colony-stimulating factor on doxorubicin resistance in MCF-7 breast cancer cells and the possible mechanism. In the study, the human breast cancer cells, MCF-7, were transfected with macrophage colony-stimulating factor. We document that cytoplasmic macrophage colony-stimulating factor induces doxorubicin resistance and inhibits apoptosis in MCF-7 cells. Further studies demonstrated that cytoplasmic macrophage colony-stimulating factor-mediated apoptosis inhibition was dependent on the activation of PI3K/Akt/Survivin pathway. More importantly, we found that macrophage colony-stimulating factor-induced autophagic cell death in doxorubicin-treated MCF-7 cells. Taken together, we show for the first time that macrophage colony-stimulating factor-induced doxorubicin resistance is associated with the changes in cell death response with defective apoptosis and promotion of autophagic cell death.

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Methotrexate induced cell death mechanisms in MCF-7 adenocarcinoma breast cancer cells: Enhanced cytotoxicity following dff45-siRNA pre-treatment

Synergy ◽

10.1016/j.synres.2018.08.002 ◽

2018 ◽

Vol 7 ◽

pp. 10-16

Author(s):

Fatemeh Kiani ◽

Negin Rasouli ◽

Tahereh Kashkoolinejad ◽

Shahrokh Safarian ◽

Seyed Jalal Zargar ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Pre Treatment ◽

Cell Death Mechanisms ◽

Mcf 7

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HDAC3–ERα Selectively Regulates TNF-α-Induced Apoptotic Cell Death in MCF-7 Human Breast Cancer Cells via the p53 Signaling Pathway

Cells ◽

10.3390/cells9051280 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1280

Author(s):

Seung-Ho Park ◽

Hyunhee Kim ◽

Sungmin Kwak ◽

Ji-Hoon Jeong ◽

Jangho Lee ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Cancer Cells ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Apoptotic Cell ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Tnf Α ◽

Mcf 7

Tumor necrosis factor-α (TNF-α) plays a significant role in inflammation and cancer-related apoptosis. We identified a TNF-α-mediated epigenetic mechanism of apoptotic cell death regulation in estrogen receptor-α (ERα)-positive human breast cancer cells. To assess the apoptotic effect of TNF-α, annexin V/ propidium iodide (PI) double staining, cell viability assays, and Western blotting were performed. To elucidate this mechanism, histone deacetylase (HDAC) activity assay and immunoprecipitation (IP) were conducted; the mechanism was subsequently confirmed through chromatin IP (ChIP) assays. Finally, we assessed HDAC3–ERα-mediated apoptotic cell death after TNF-α treatment in ERα-positive human breast cancer (MCF-7) cells via the transcriptional activation of p53 target genes using luciferase assay and quantitative reverse transcription PCR. The TNF-α-induced selective apoptosis in MCF-7 cells was negatively regulated by the HDAC3–ERα complex in a caspase-7-dependent manner. HDAC3 possessed a p53-binding element, thus suppressing the transcriptional activity of its target genes. In contrast, MCF-7 cell treatment with TNF-α led to dissociation of the HDAC3–ERα complex and substitution of the occupancy on the promoter by the p53–p300 complex, thus accelerating p53 target gene expression. In this process, p53 stabilization was accompanied by its acetylation. This study showed that p53-mediated apoptosis in ERα-positive human breast cancer cells was negatively regulated by HDAC3–ERα in a caspase-7-dependent manner. Therefore, these proteins have potential application in therapeutic strategies.

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Polyamines modulate the roscovitine-induced cell death switch decision autophagy vs. apoptosis in MCF-7 and MDA-MB-231 breast cancer cells

Molecular Medicine Reports ◽

10.3892/mmr.2015.3303 ◽

2015 ◽

Vol 11 (6) ◽

pp. 4532-4540 ◽

Cited By ~ 6

Author(s):

ELIF DAMLA ARISAN ◽

YUNUS AKKOÇ ◽

KAAN GENCER AKYÜZ ◽

EZGI MELEK KERMAN ◽

PINAR OBAKAN ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Mcf 7

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Differential expression of microRNA expression in tamoxifen-sensitive MCF-7 versus tamoxifen-resistant LY2 human breast cancer cells

Cancer Letters ◽

10.1016/j.canlet.2011.08.018 ◽

2011 ◽

Vol 313 (1) ◽

pp. 26-43 ◽

Cited By ~ 51

Author(s):

Tissa T. Manavalan ◽

Yun Teng ◽

Savitri N. Appana ◽

Susmita Datta ◽

Theodore S. Kalbfleisch ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Differential Expression ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Microrna Expression ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Tamoxifen Resistant ◽

Mcf 7

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MEK activity controls IL-8 expression in tamoxifen-resistant MCF-7 breast cancer cells

Oncology Reports ◽

10.3892/or.2016.4557 ◽

2016 ◽

Vol 35 (4) ◽

pp. 2398-2404 ◽

Cited By ~ 3

Author(s):

SANGMIN KIM ◽

MYEONGJIN JEON ◽

JEONG EON LEE ◽

SEOK JIN NAM

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tamoxifen Resistant ◽

Mcf 7

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Inhibition of STAT3 enhances sensitivity to tamoxifen in tamoxifen-resistant breast cancer cells

BMC Cancer ◽

10.1186/s12885-021-08641-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Seo Yun Moon ◽

Heejin Lee ◽

Seoree Kim ◽

Ji Hyung Hong ◽

Sang Hoon Chun ◽

...

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Signalling Pathway ◽

Expression Levels ◽

Er Positive ◽

Tamoxifen Resistant ◽

Stat3 Signalling ◽

Mcf 7

Abstract Background The mechanisms of endocrine resistance are complex, and deregulation of several oncogenic signalling pathways has been proposed. We aimed to investigate the role of the EGFR and Src-mediated STAT3 signalling pathway in tamoxifen-resistant breast cancer cells. Methods The ER-positive luminal breast cancer cell lines, MCF-7 and T47D, were used. We have established an MCF-7-derived tamoxifen-resistant cell line (TamR) by long-term culture of MCF-7 cells with 4-hydroxytamoxifen. Cell viability was determined using an MTT assay, and protein expression levels were determined using western blot. Cell cycle and annexin V staining were analysed using flow cytometry. Results TamR cells showed decreased expression of estrogen receptor and increased expression of EGFR. TamR cells showed an acceleration of the G1 to S phase transition. The protein expression levels of phosphorylated Src, EGFR (Y845), and STAT3 was increased in TamR cells, while phosphorylated Akt was decreased. The expression of p-STAT3 was enhanced according to exposure time of tamoxifen in T47D cells, suggesting that activation of STAT3 can cause tamoxifen resistance in ER-positive breast cancer cells. Both dasatinib (Src inhibitor) and stattic (STAT3 inhibitor) inhibited cell proliferation and induced apoptosis in TamR cells. However, stattic showed a much stronger effect than dasatinib. Knockdown of STAT3 expression by siRNA had no effect on sensitivity to tamoxifen in MCF-7 cells, while that enhanced sensitivity to tamoxifen in TamR cells. There was not a significant synergistic effect of dasatinib and stattic on cell survival. TamR cells have low nuclear p21(Cip1) expression compared to MCF-7 cells and inhibition of STAT3 increased the expression of nuclear p21(Cip1) in TamR cells. Conclusions The EGFR and Src-mediated STAT3 signalling pathway is activated in TamR cells, and inhibition of STAT3 may be a potential target in tamoxifen-resistant breast cancer. An increase in nuclear p21(Cip1) may be a key step in STAT3 inhibitor-induced cell death in TamR cells.

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