scholarly journals Disruption of pH Dynamics Suppresses Proliferation and Potentiates Doxorubicin Cytotoxicity in Breast Cancer Cells

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 242
Author(s):  
Diana Tavares-Valente ◽  
Bárbara Sousa ◽  
Fernando Schmitt ◽  
Fátima Baltazar ◽  
Odília Queirós
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Human Breast ◽  
Cancer Tissues ◽  
Mcf 7

The reverse pH gradient is a major feature associated with cancer cell reprogrammed metabolism. This phenotype is supported by increased activity of pH regulators like ATPases, carbonic anhydrases (CAs), monocarboxylate transporters (MCTs) and sodium–proton exchangers (NHEs) that induce an acidic tumor microenvironment, responsible for the cancer acid-resistant phenotype. In this work, we analyzed the expression of these pH regulators and explored their inhibition in breast cancer cells as a strategy to enhance the sensitivity to chemotherapy. Expression of the different pH regulators was evaluated by immunofluorescence and Western blot in two breast cancer cell lines (MDA-MB-231 and MCF-7) and by immunohistochemistry in human breast cancer tissues. Cell viability, migration and invasion were evaluated upon exposure to the pH regulator inhibitors (PRIs) concanamycin-A, cariporide, acetazolamide and cyano-4-hydroxycinnamate. Additionally, PRIs were combined with doxorubicin to analyze the effect of cell pH dynamic disruption on doxorubicin sensitivity. Both cancer cell lines expressed all pH regulators, except for MCT1 and CAXII, only expressed in MCF-7 cells. There was higher plasma membrane expression of the pH regulators in human breast cancer tissues than in normal breast epithelium. Additionally, pH regulator expression was significantly associated with different molecular subtypes of breast cancer. pH regulator inhibition decreased cancer cell aggressiveness, with a higher effect in MDA-MB-231. A synergistic inhibitory effect was observed when PRIs were combined with doxorubicin in the breast cancer cell line viability. Our results support proton dynamic disruption as a breast cancer antitumor strategy and the use of PRIs to boost the activity of conventional therapy.

scholarly journals MARCH8 Suppresses Tumor Metastasis and Mediates Degradation of STAT3 and CD44 in Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2550
Author(s):  
Wenjing Chen ◽  
Dhwani Patel ◽  
Yuzhi Jia ◽  
Zihao Yu ◽  
Xia Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Human Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Human Breast

Protein stability is largely regulated by post-translational modifications, such as ubiquitination, which is mediated by ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2, and ubiquitin ligase E3 with substrate specificity. Membrane-associated RING-CH (MARCH) proteins represent one novel family of transmembrane E3 ligases which target glycoproteins for lysosomal destruction. While most of the MARCH family members are known to degrade membrane proteins in immune cells, their tumor-intrinsic role is largely unknown. In this study, we found that the expression of one MARCH family member, MARCH8, is specifically downregulated in breast cancer tissues and positively correlated with breast cancer survival rate according to bioinformatic analysis of The Cancer Genomic Atlas (TCGA) dataset. MARCH8 protein expression was also lower in a variety of human breast cancer cell lines in comparison to immortalized human mammary epithelial MCF-12A cells. Restoration of MARCH8 expression induced apoptosis in human breast cancer cell lines MDA-MB-231 and BT549. Stable expression of MARCH8 inhibited tumorigenesis and lung metastases of MDA-MB-231 cells in mice. Moreover, we discovered that the breast cancer stem-cell marker and metastasis driver CD44, a membrane protein, interacts with MARCH8 and is one of the glycoprotein targets subject to MARCH8-dependent lysosomal degradation. Unexpectedly, we identified a nonmembrane protein, signal transducer and transcription activator 3 (STAT3), as another essential ubiquitination target of MARCH8, whose degradation through the proteasome pathway is responsible for the proapoptotic changes mediated by MARCH8. These findings highlight a novel tumor-suppressing function of MARCH8 in targeting both membrane and nonmembrane protein targets required for the survival and metastasis of breast cancer cells.

scholarly journals Long non-coding RNA LINC00662 promotes proliferation and migration of breast cancer cells via regulating the miR-497-5p/EglN2 axis

2020 ◽  
Author(s):  
Wuqin Xu ◽  
Zihe Xing ◽  
Peng Zhang ◽  
Wuqin Xu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Human Breast

Previous reports indicated that long noncoding RNA 662 (LINC00662) plays a crucial role in several human cancers. Here, we studied the expression pattern of LINC00662 and explored its function in human breast cancer. The expression level of LINC00662 was determined in human breast cancer cell lines and tissues by real-time quantitative polymerase chain reaction (RT-qPCR). Cytoplasmic and nuclear RNA from MDA-MB-157 cells were extracted to analyze the subcellular location of LINC00662. Moreover, the MTT assay, wound-healing assay, colony-forming assay and transwell assay were employed in MDA-MB-157 cells to detect the effect of LINC00662 on cell apoptosis, invasion, migration and proliferation, respectively. LINC00662-specific miRNA and miRNA-gene axis were examined in a dual-luciferase reporter assay and Western blot. We found that LINC00662 was overexpressed in both breast cancer cell lines and tissue compared to normal breast cell lines and healthy breast tissue. Analysis of subcellular localization revealed that LINC00662 was mainly found in the cytoplasm. Furthermore, LINC00662 silencing reduced cell viability and inhibited the proliferation, migration and invasion of MDA-MB-157 cells. Bioinformatics analysis predicted that LNC00662 binds to miR-497-5p. A series of studies confirmed that LINC00662 directly interacted with miR-497-5p and downregulated its expression in MDA-MB-157 cells. MiR-497-5p knockdown significantly reversed the inhibitory effect of shLINC00662. Moreover, egl-9 family hypoxia inducible factor 2 (EglN2) was verified as a target of miR-497-5p. Overall, our results demonstrated that overexpression of LINC00662 accelerated the malignant growth of breast cancer cells via sponging miR-497-5p and upregulating EglN2 expression, and indicate that targeting LINC00662 may represent a novel strategy for breast cancer therapy.

scholarly journals The connection of miR-21 and miR-155 with regulation of 15-HPGDH mRNA in human breast cancer cells

2016 ◽  
Vol 62 (3) ◽  
pp. 265-271 ◽  
Author(s):  
Z.N. Nikiforova ◽  
M.A. Taipov ◽  
I.A. Kudryavcev ◽  
V.E. Shevchenko
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Human Breast Cancer ◽  
Breast Cancer Cell Lines ◽  
Human Breast ◽  
Cox 2 ◽  
Mcf 7

Breast cancer is the most frequent cancer and the leading cause of cancer-related deaths in women worldwide. We determined the expression of COX2, COX1, 15-HPGDH mRNA and miRNAs (miR-21, miR-155) in three estrogen positive human breast cancer cell lines (MCF-7, BT-474, ZR-75-1). According to the results of three independent experiments the amount of COX1 and COX2 mRNA was significantly higher in the ZR-75-1 than in MCF-7 and BT-474 cells. Levels of total 15-HPGDH; functional 15-HPGDH mRNA in BT-474 cell line were lower than in MCF-7 and ZR-75-1 ones. The synthesis of 15-HPGDH enzyme in BT-474 line was blocked at the nuclear immature pre-mRNA processing level. miR-155 expression level was significantly lower than miR-21 in breast cancer cell lines. Correlations between the dysregulation of miR-21, miR-155 and 15-HPGDH, COX-1, COX-2 mRNA were identified. Expression of miR-21 was high in MCF-7, ZR-75-1 and BT-474 cell lines. Our results show that miR-21 and miR-155 regulate activity of several genes in cancer cells, their effect on the individual genes was in some cases cumulative. Based on our results, we concluded that miR-21, miR-155 suppress the work of tumor suppressor gene 15-HPGDH and induce potential oncogene COX-2 that promotes cell malignancy and metastasis of breast cancer.

scholarly journals ERβ-induced MFN2 inhibits the migration and invasiveness of breast cancer cells by inhibiting the P-AKT signaling pathway

2020 ◽  
Author(s):  
Mengyu Wei ◽  
Jun Hao ◽  
Xiaomei Liao ◽  
Yinfeng Liu ◽  
Ruihuan Fu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Akt Pathway ◽  
Cancer Cell Migration ◽  
Breast Cancer Patients ◽  
Human Breast ◽  
Mcf 7

Abstract Background Mitofusin 2 (MFN2) is localized on the outer membrane of mitochondria and is closely related to the migration of malignant tumor cells. Estrogen receptor β (ERβ) plays an anticancer role in breast cancer. Our previous experiments showed that ERβ can induce MFN2 expression, which then inhibits breast cancer cell migration. However, the exact mechanism by which ERβ-induced MFN2 inhibits breast cancer cell migration is unknown. Methods In this study, immunohistochemistry was first used to detect the expression of MFN2 in breast cancer tissues, and its relationship with the clinicopathological characteristics and prognosis of breast cancer patients was analyzed. MCF-7 and MDA-MB-231 cells were transfected with ERβ and MFN2 knockdown or expression plasmids. Western blot was used to detect the effects of ERβ on MFN2 and MFN2 on P-AKT473 and MMP2; the P-AKT pathway inhibitor LY294002 was administered to cells transfected with MFN2 knockdown plasmids, Western blot, immunocytofluorescence, and a wound healing assay revealed the effect of MFN2 on its downstream signaling pathway and the migration of breast cancer cells. Results This study found that the expression of MFN2 is related to the molecular type and prognosis of breast cancer patients ( P <0.05). The positive expression rate of MFN2 in triple-negative breast cancer was significantly lower than that in the HER2 + and luminal types. However, MFN2 expression was unrelated to age, tumor size, lymph node metastasis, TNM stage, histological type and grade ( P >0.05); ERβ positively regulated MFN2 expression and reduced the migration of both MCF-7 and MDA-MB-231 cells, while MFN2 knockdown increased the expression of P-AKT473 and MMP2. In contrast, the overexpression of MFN2 inhibited the expression of P-AKT473 and MMP2. These results showed that in MFN2 knockdown cells treated with LY294002, P-AKT473 and MMP2 expression levels were reversed. The reversal of P-AKT473 and MMP2 expression levels inhibits the invasiveness of human breast cancer cells. Conclusion MFN2 is related to the molecular subtype and prognosis of breast cancer. In human breast cancer MCF-7 and MDA-MB-231 cells, ERβ-induced MFN2 can inhibit the P-AKT pathway, which inhibits the invasiveness and migration of both breast cancer cell lines.

scholarly journals The role of miRNAs 34a, 146a, 320a and 542 in the synergistic anticancer effects of methyl 2-(5-fluoro-2-hydroxyphenyl)-1H- benzo[d]imidazole-5-carboxylate (MBIC) with doxorubicin in breast cancer cells

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5577 ◽  
Author(s):  
Mohadeseh Hasanpourghadi ◽  
Nazia Abdul Majid ◽  
Mohd Rais Mustafa
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Human Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Human Breast ◽  
Mcf 7

Combination Index (CI) analysis suggested that MBIC and doxorubicin synergistically inhibited up to 97% of cell proliferation in ER+/PR+MCF-7 and triple negative MDA-MB-231 breast cancer cell lines. Moreover, treatment of the breast cancer cells with the combined drugs resulted in lower IC50 values in contrast to the individual drug treatment. Small noncoding microRNAs (miRNA) may function as non-mutational gene regulators at post-transcriptional level of protein synthesis. In the present study, the effect of the combined treatment of MBIC and doxorubicin on the expression level of several miRNAs including miR-34a, miR-146a, miR-320a and miR-542 were evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines. These miRNAs have the potential to alter the protein level of survivin, the anti-apoptotic protein and reduce the metastatic activity in human breast cancer cell lines by interfering with the nuclear accumulation of NF-κB. Our results demonstrated the several fold changes in expression of miRNAs, which is drug and cell line dependent. This finding demonstrated a functional synergistic network between miR-34a, miR-320a and miR-542 that are negatively involved in post-transcriptional regulation of survivin in MCF-7 cells. While in MDA-MB-231 cells, changes in expression level of miR-146a was correlated with inhibition of the nuclear translocation of NF-κB. The overall result suggested that alteration in protein level and location of survivin and NF-κB by miR-34a, miR-320a, miR-146a and miR-542, remarkably influenced the synergistic enhancement of combined MBIC and doxorubicin in treatment of aggressive and less aggressive human breast cancer cell lines.

In Vitro and In Silico Determination of some N-ferrocenylmethylaniline Derivatives as Anti-Proliferative Agents against MCF-7 Human Breast Cancer Cell Lines

2021 ◽  
Vol 21 ◽  
Author(s):  
Nadjiba Zegheb ◽  
Cherifa Boubekri ◽  
Touhami Lanez ◽  
Elhafnaoui Lanez ◽  
Tuba Tüylü Küçükkılınç ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Proliferative Activity ◽  
Human Breast Cancer ◽  
Breast Cancer Cell Lines ◽  
Human Breast ◽  
Ferrocene Derivatives ◽  
Mcf 7

Background: Since the binding of estradiol to its receptor promotes breast cancer cell proliferation (in the ER+ tumours), many molecules targeting this protein have been synthesized to counteract the estradiol action. Ferrocene derivatives have proved their efficiency against hormone-dependent breast cancer cells (MCF-7). Objective: In this study, we aimed to find new ferrocene derivatives having pharmacochemistry properties as potential drugs against human breast cancer cells. Methods: A series of 29 N-ferrocenylmethylaniline derivatives A0-A28 were synthesised, and their anti-proliferative activity against both hormone-dependent (MCF-7) and independent (MDA-MB 231) human breast cancer cell lines were performed using the MTT test. Molecular docking and drug-likeness prediction were also performed for the five most active derivatives towards MCF-7. A QSAR model was also developed for the perdition of the anti-proliferative activity against MCF-7 cell lines using molecular descriptors and MLR analysis. Results: All studied derivatives demonstrated better cytotoxicity against MCF-7 compared to the MDA-MB-231 cell lines, and compounds A2, A9, A14, A17, and A27 were the most potent ones; however, but still less active than the standard anti-cancer drug crizotinib. The QSAR study revealed good predictive ability as shown by R2cv = 0.848. Conclusion: In vitro and in silico results indicated that derivatives A2, A9, A14, A17, and A27 possess the highest anti-proliferative activity, t. These results can be used to design more potent N-ferrocenylmethylaniline derivatives as anti-proliferative agents.

scholarly journals New Isoflavanes from Spatholobus suberectus and Their Cytotoxicity against Human Breast Cancer Cell Lines

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3218 ◽  
Author(s):  
Fu Peng ◽  
Huan Zhu ◽  
Chun-Wang Meng ◽  
Yan-Rui Ren ◽  
Ou Dai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Human Breast Cancer ◽  
Human Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Human Breast ◽  
Spatholobus Suberectus ◽  
Mcf 7

The rattans of Spatholobus suberectus Dunn are a traditional Chinese medicine activating blood circulation and removing stasis. They have often been used for the traditional Chinese medicinal treatment of breast cancer in modern China. In this study, four novel isoflavanes (1–3 and 5) and four known analogues (4 and 6–8) were isolated from an ethanolic extract of the rattans of S. suberectus. Their structures were elucidated by extensive spectroscopic analyses and electronic circular dichroism studies. MCF-7 and MDA-MB-231 human breast cancer cell lines were used to evaluate the cytotoxic effects of the isolates. Interestingly, compounds 1 and 2 only inhibited the proliferation of MCF-7 cells, while compound 6 showed a selective cytotoxicity against MDA-MB-231 cells. However, compound 4 had significant cytotoxicity against both MCF-7 and MDA-MB-231 cell lines.

Sign in / Sign up

Export Citation Format

Share Document