Impaired Expression of Cytoplasmic Actins Leads to Chromosomal Instability of MDA-MB-231 Basal-Like Mammary Gland Cancer Cell Line.
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ABSTRACT:
SUBMITTER: Dugina V
PROVIDER: S-EPMC8068389 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Since bone metastatic breast cancer is an incurable disease, causing significant morbidity and mortality, understanding of the underlying molecular mechanisms would be highly valuable. Here, we describe in vitro and in vivo evidence for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic and histological observations in the inoculated mice. Genome-wide gene expression profiling of this isogenic cell line pair revealed that all the three genes involved in the L-serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) were upregulated in the highly metastatic variant. This pathway is the primary endogenous source for L-serine in mammalian tissues. Consistently, we observed that the proliferation of MDA-MB-231(SA) cells in serine-free conditions was dependent on PSAT1 expression. In addition, we observed that L-serine is essential for the formation of bone resorbing human osteoclasts and may thus contribute to the vicious cycle of osteolytic bone metastasis. High expression of PHGDH and PSAT1 in primary breast cancer was significantly associated with decreased relapse-free and overall survival of patients and malignant phenotypic features of breast cancer. In conclusion, high expression of serine biosynthesis genes in metastatic breast cancer cells and the stimulating effect of L-serine on osteoclastogenesis and cancer cell proliferation indicate a functionally critical role for serine biosynthesis in bone metastatic breast cancer and thereby an opportunity for targeted therapeutic interventions. Parental MDA-MB-231 cells and MDA-MB-231(SA) cells were cultured in cell culture flasks. RNA was isolated in order to compare the gene expression profiles of these cell variants. Total of two samples. No replicates.
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Project description:In the past decades, altered Follistatin‑like 1 (FSTL1) expression has been documented in a variety of cancers, while its functional roles are poorly understood. Particularly in breast cancer, the expression of FSTL1 and its signaling pathway remain to be determined. In the present study, an elevated FSTL1 expression and a supressed cell proliferation were detected in a specific brain metastatic cell line MDA‑MB‑231‑BR (231‑BR), compared with its parental cell line MDA‑MB‑231. However, this protein was hardly detected in the other three breast cancer cell lines. Next, lentiviral vectors encoding FSTL1 or FSTL1 specific shRNAs were used to overexpress or knock down FSTL1 in MDA‑MB‑231 or 231‑BR, respectively (MDA‑MB‑231FSTL1 or 231‑BRsh FSTL1). Results showed that overexpression of FSTL1 inhibited MDA‑MB‑231 cell proliferation, while knockdown of FSTL1 in 231‑BR cells promotes cell proliferation, compared with their corresponding control groups. These results were further confirmed in nude mouse xenografts. The tumor volume in 231‑BR cell-bearing mice was significantly smaller than that of MDA‑MB‑231 group, and reduction of tumor volume was detected in MDA‑MB‑231FSTL1 cell-bearing mice compared with the control group. Previous studies revealed that TGF‑β-Smad2/3 signaling pathway was activated in 231‑BR and MDA‑MB‑231FSTL1 cells, which may contribute to the inhibited cell proliferation. In addition, Smad3 knockdown could restore the inhibition of cell proliferation induced by FSTL1 overexpression in MDA‑MB‑231FSTL1 cells, indicating that the anti‑proliferative effect of FSTL1 overexpression may be associated with Smad3 involved TGF‑β signaling pathway regulation. This study identified FSTL1 as an inhibitor of cell proliferation in MDA‑MB‑231 and 231‑BR cell lines, which may provide new insights into the development and management of breast cancer.
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Project description:Breast cancer remains a leading cause of death in women worldwide. Although breast cancer therapies have greatly advanced in recent years, many patients still develop tumour recurrence and metastasis, and eventually succumb to the disease due to chemoresistance. Citral has been reported to show cytotoxic effect on various cancer cell lines. However, the potential of citral to specifically target the drug resistant breast cancer cells has not yet been tested, which was the focus of our current study.The cytotoxic activity of citral was first tested on MDA-MB-231 cells in vitro by MTT assay. Subsequently, spheroids of MDA-MB-231 breast cancer cells were developed and treated with citral at different concentrations. Doxorubicin, cisplatin and tamoxifen were used as positive controls to evaluate the drug resistance phenotype of MDA-MB-231 spheroids. In addition, apoptosis study was performed using AnnexinV/7AAD flowcytometry. Aldefluor assay was also carried out to examine whether citral could inhibit the ALDH-positive population, while the potential mechanism of the effect of citral was carried out by using quantitative real time- PCR followed by western blotting analysis.Citral was able to inhibit the growth of the MDA-MB-231 spheroids when compared to a monolayer culture of MDA-MB-231 cells at a lower IC50 value. To confirm the inhibition of spheroid self-renewal capacity, the primary spheroids were then cultured to additional passages in the absence of citral. A significant reduction in the number of secondary spheroids were formed, suggesting the reduction of self-renewal capacity of these aldehyde dehydrogenase positive (ALDH+) drug resistant spheroids. Moreover, the AnnexinV/7AAD results demonstrated that citral induced both early and late apoptotic changes in a dose-dependent manner compared to the vehicle control. Furthermore, citral treated spheroids showed lower cell renewal capacity compared to the vehicle control spheroids in the mammosphere formation assay. Gene expression studies using quantitative real time PCR and Western blotting assays showed that citral was able to suppress the self-renewal capacity of spheroids and downregulate the Wnt/?-catenin pathway.The results suggest that citral could be a potential new agent which can eliminate drug-resistant breast cancer cells in a spheroid model via inducing apoptosis.
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Project description:Because of differences in the downstream signaling patterns of its pathways, the role of the human epidermal growth factor family of receptors (HER) in promoting cell growth and survival is cell line and context dependent. Using two model cell lines, we have studied how the regulatory interaction network among the key proteins of HER signaling pathways may be rewired upon normal to cancerous transformation. We in particular investigated how the transcription factor STAT3 and several key kinases' involvement in cancer-related signaling processes differ between normal 184A1L5 human mammary epithelial (HME) and MDA-MB-231 breast cancer epithelial cells. Comparison of the responses in these cells showed that normal-to-cancerous cellular transformation causes a major re-wiring of the growth factor initiated signaling. In particular, we found that: i) regulatory interactions between Erk, p38, JNK and STAT3 are triangulated and tightly coupled in 184A1L5 HME cells, and ii) STAT3 is only weakly associated with the Erk-p38-JNK pathway in MDA-MB-231 cells. Utilizing the concept of pathway substitution, we predicted how the observed differences in the regulatory interactions may affect the proliferation/survival and motility responses of the 184A1L5 and MDA-MB-231 cells when exposed to various inhibitors. We then validated our predictions experimentally to complete the experiment-computation-experiment iteration loop. Validated differences in the regulatory interactions of the 184A1L5 and MDA-MB-231 cells indicated that instead of inhibiting STAT3, which has severe toxic side effects, simultaneous inhibition of JNK together with Erk or p38 could be a more effective strategy to impose cell death selectively to MDA-MB-231 cancer cells while considerably lowering the side effects to normal epithelial cells. Presented analysis establishes a framework with examples that would enable cell signaling researchers to identify the signaling network structures which can be used to predict the phenotypic responses in particular cell lines of interest.
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Project description:MiR-544 was inhibited by either a miR-544 antagomir or compound 1 under hypoxic conditions in MDA-MB-231 cells MiRNA microarray was utilized to examine the specificity of 1 for miR-544. 3 MDA-MB-231 samples treated with a miR-544 antagomir or compound 1 were subjected to hypoxia for a period of 5 days. After 5 days, samples were pooled and subjected to miRNA microarray analysis.
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Project description:Elastin is a long-lived extracellular matrix protein responsible for the structural integrity and function of tissues. Breast cancer elastosis is a complex phenomenon resulting in both the deposition of elastotic masses and the local production of elastin fragments. In invasive human breast cancers, an increase in elastosis is correlated with severity of the disease and age of the patient. Elastin-derived peptides (EDPs) are a hallmark of aging and are matrikines - matrix fragments having the ability to regulate cell physiology. They are known to promote processes linked to tumor progression, but their effects on breast cancer cells remain unexplored. Our data show that EDPs enhance the invasiveness of MDA-MB-231 breast cancer cells through the engagement of matrix metalloproteases 14 and 2. We therefore suggest that elastosis and/or an aged stroma could promote breast cancer cell invasiveness.
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Project description:Shock waves are gaining interests in biological and medical applications. In this work, we investigated the mechanical characteristics of shock waves that affect cell viability. In vitro testing was conducted using the metastatic breast epithelial cell line MDA-MB-231. Shock waves were generated using a high-power pulse laser. Two different coating materials and different laser energy levels were used to vary the peak pressure, decay time, and the strength of subsequent peaks of the shock waves. Within the testing capability of the current study, it is shown that shock waves with a higher impulse led to lower cell viability, a higher detached cell ratio, and a higher cell death ratio, while shock waves with the same peak pressure could lead to different levels of cell damage. The results also showed that the detached cells had a higher cell death ratio compared to the attached cells. Moreover, a critical shock impulse of 5 Pa·s was found to cause the cell death ratio of the detached cells to exceed 50%. This work has demonstrated that, within the testing range shown here, the impulse, rather than the peak pressure, is the governing shock wave parameter for the damage of MDA-MB-231 breast cancer cells. The result suggests that a lower-pressure shock wave with a longer duration, or multiple sequential low amplitude shock waves can be applied over a duration shorter than the fundamental response period of the cells to achieve the same impact as shock waves with a high peak pressure but a short duration. The finding that cell viability is better correlated with shock impulse rather than peak pressure has potential significant implications on how shock waves should be tailored for cancer treatments, enhanced drug delivery, and diagnostic techniques to maximize efficacy while minimizing potential side effects.
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Project description:BackgroundThe diverse specificity mode of cancer treatment targets and chemo resistance demands the necessity of drug entities which can address the devastating dynamicity of the disease.ObjectivesTo check the anti-tumour potential of traditional medicine rich in polyherbal components and metal nanoparticle namely Arkeshwara rasa (AR).Material methodsThe AR was prepared in a modified version with reference from Rasaratna Samuchaya and characterized using sophisticated instrumental analysis including XRD, SEM-EDAX, TEM, TGA-DSC, and LC-MS and tested against the MDA-MB-231 cell line to screen cell viability and the cytotoxicity with MTT, SRB and the AO assay.ResultsXRD pattern shows cubic tetrahedrite structure with Sb, Cu, S peaks and trace elements like Fe, Mg, etc. The particle size of AR ranges between 20 and 30 nm. The TGA points thermal decomposition at 210 °C and the metal sulphide peaks in DSC. LC-MS analysis reveals the components of the formulation more on the flavonoid portion. The IC50 value of MTT and SRB are 25.28 μg/mL and 31.7 μg/mL respectively. The AO colorimeter substantiated the cell viability and the apoptosis figures of the same cell line. The AR exhibits cytotoxicity and reaffirms the apoptosis fraction with SRB assay.ConclusionsThe Hesperidine, Neohesperidin, Rutin components in the phytochemical pool can synergize the anti-tumour potential with either influencing cellular pathways or decreasing chemo resistance to conventional treatment. AR need to be further experimented with reverse transcription, flow cytometry, western blotting, etc.
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Project description:Successful adhesion of circulating tumor cells (CTCs) to microvascular endothelium of distant metastatic tissue is the key starting step of metastatic cascade that could be effectively chemoprevented as we demonstrated previously. Here, we hypothesize that the hetero-adhesion may produce secretory biomarkers that may be important for both premetastatic diagnosis and chemoprevention. We show that co-incubation of triple-negative breast cancer (TNBC) cell line MDA-MB-231 with human pulmonary microvascular endothelial monolayers (HPMEC) secretes Cyr61 (CCN1), primarily from MDA-MB-231. However, addition of metapristone (RU486 metabolite) to the co-incubation system inhibits Cyr61 secretion probably via the Cyr61/integrin αvβ1 signaling pathway without significant cytotoxicity on both MDA-MB-231 and HPMEC. Transfection of MDA-MB-231 with Cyr61-related recombinant plasmid or siRNA enhances or reduces Cyr61 expression, accordingly. The transfection significantly changes hetero-adhesion and migration of MDA-MB-231, and the changed bioactivities by overexpressed CYR61 could be antagonized by metapristone in vitro. Moreover, the circulating MDA-MB-231 develops lung metastasis in mice, which could be effectively prevented by oral metapristone without significant toxicity. The present study, for the first time, demonstrates that co-incubation of MDA-MB-231 with HPMEC secrets CYR61 probably via the CYR61/integrin αvβ1 signaling pathway to promote adhesion-invasion of TNBC (early metastatic step). Metapristone, by interfering the adhesion-invasion process, prevents metastasis from happening.
| S-EPMC6880622 | biostudies-literature
Project description:(1) Background: Amikacin is an aminoglycoside antibiotic used for treating gram-negative bacterial infections in cancer patients. In this study, our aims are to investigate the migratory inhibition effects of amikacin in human MDA-MB-231 cells. (2) Methods: We used a wound-healing assay, trans-well analysis, Western blotting, immunostaining and siRNA knockdown approaches to investigate how amikacin influenced MDA-MB-231 cell migration and invasion. (3) Results: Wound healing showed that the MDA-MB-231 cell migration rates decreased to 44.4% in the presence of amikacin. Trans-well analysis showed that amikacin treatment led to invasion inhibition. Western blotting demonstrated that amikacin induced thioredoxin-interacting protein (TXNIP) up-regulation. TXNIP was knocked down using siRNA in MDA-MB-231 cell. Using immunostaining analysis, we found that inhibition of TXNIP expression led to MDA-MB-231 pseudopodia extension; however, amikacin treatment attenuated the cell extension formation. (4) Conclusions: We observed inhibition of migration and invasion in MDA-MB-231 cells treated with amikacin. This suggests inhibition might be mediated by up-regulation of TXNIP.
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