Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Fernandez-Cabezudo MJ
PROVIDER: S-EPMC4888911 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BACKGROUND:Claudin-6 (CLDN6), a member of CLDN family and a key component of tight junction, has been reported to function as a tumor suppressor in breast cancer. However, whether CLDN6 plays any role in breast cancer chemoresistance remains unclear. In this study, we investigated the role of CLDN6 in the acquisition of chemoresistance in breast cancer cells. METHODS:We manipulated the expression of CLDN6 in MCF-7 and MCF-7/MDR cells with lv-CLDN6 and CLDN6-shRNA and investigated whether CLDN6 manipulation lead to different susceptibilities to several chemotherapeutic agents in these cells. The cytotoxicity of adriamycin (ADM), 5-fluorouracil (5-FU), and cisplatin (DDP) was tested by cck-8 assay. Cell death was determined by DAPI nuclear staining. The enzyme activity of glutanthione S-transferase-p1 (GSTP1) was detected by a GST activity kit. Then lv-GSTP1 and GSTP1-shRNA plasmids were constructed to investigate the potential of GSTP1 in regulating chemoresistance of breast cancer. The TP53-shRNA was adopted to explore the regulation mechanism of GSTP1. Finally, immunohistochemistry was used to explore the relationship between CLDN6 and GSTP1 expression in breast cancer tissues. RESULTS:Silencing CLDN6 increased the cytotoxicity of ADM, 5-FU, and DDP in MCF-7/MDR cells. Whereas overexpression of CLDN6 in MCF-7, the parental cell line of MCF-7/MDR expressing low level of CLDN6, increased the resistance to the above drugs. GSTP1 was upregulated in CLDN6-overexpressed MCF-7 cells. RNAi -mediated silencing of CLDN6 downregulated both GSTP1 expression and GST enzyme activity in MCF-7/MDR cells. Overexpresssion of GSTP1 in CLDN6 silenced MCF-7/MDR cells restored chemoresistance, whereas silencing GSTP1 reduced the chemoresistance due to ectopic overexpressed of CLDN6 in MCF-7 cells. These observations were also repeated in TNBC cells Hs578t. We further confirmed that CLDN6 interacted with p53 and promoted translocation of p53 from nucleus to cytoplasm, and both the expression and enzyme activity of GSTP1 were regulated by p53. Clinicopathologic analysis revealed that GSTP1 expression was positively associated with CLDN6 in human breast cancer samples. CONCLUSION:High expression of CLDN6 confers chemoresistance on breast cancer which is mediated by GSTP1, the activity of which is regulated by p53. Our findings provide a new insight into mechanisms and strategies to overcome chemoresistance in breast cancer.
| S-EPMC5678781 | biostudies-literature
Project description:Chemoresistance remains a major obstacle to successful treatment of breast cancer. Although soluble tumor necrosis factor-α (sTNF-α) has been implicated in mediating drug-resistance in human cancers, whether transmembrane tumor necrosis factor-α (tmTNF-α) plays a role in chemoresistance remains unclear. Here we found that over 50% of studied patients expressed tmTNF-α at high levels in breast cancer tissues and tmTNF-α expression positively correlated with resistance to anthracycline chemotherapy. Alteration of tmTNF-α expression changed the sensitivity of primary human breast cancer cells and breast cancer cell lines to doxorubicin (DOX). Overexpression of N-terminal fragment (NTF) of tmTNF-α, a mutant form with intact intracellular domain of tmTNF-α to transmit reverse signals, induced DOX-resistance. Mechanistically, the tmTNF-α/NTF-ERK-GST-π axis and tmTNF-α/NTF-NF-κB-mediated anti-apoptotic functions were required for tmTNF-α-induced DOX-resistance. In a xenograft mouse model, the combination of tmTNF-α suppression with chemotherapy significantly enhanced the efficacy of DOX. Our data indicate that tmTNF-α mediates DOX-resistance through reverse signaling and targeting tmTNF-α may be beneficial for the treatment of DOX-resistant breast cancer.
| S-EPMC6013421 | biostudies-literature
Project description:BackgroundThe transfer of whole mitochondria that occurs during cell contact has been found to support cancer progression. However, the regulatory role of mitochondria alone is difficult to elucidate due to the complex microenvironment. Currently, mitochondrial transplantation is an available approach for restoring mitochondrial function in mitochondrial diseases but remains unclear in breast cancer. Herein, effects of mitochondrial transplantation via different approaches in breast cancer were investigated.MethodsWhole mitochondria (approximately 10.5 μg/ml) were transported into MCF-7 breast cancer cells via passive uptake or Pep-1-mediated delivery. Fresh mitochondria isolated from homeoplasmic 143B osteosarcoma cybrids containing mitochondrial DNA (mtDNA) derived from health individuals (Mito) or mtDNA with the A8344G mutation (Mito8344) were conjugated with cell-penetrating peptide Pep-1 (P-Mito) or not conjugated prior to cell co-culture. Before isolation, mitochondria were stained with MitoTracker dye as the tracking label. After 3 days of treatment, cell viability, proliferation, oxidative stress, drug sensitivity to Doxorubicin/Paclitaxel and mitochondrial function were assessed.ResultsCompared with P-Mito, a small portion of Mito adhered to the cell membrane, and this was accompanied by a slightly lower fluorescent signal by foreign mitochondria in MCF-7 cells. Both transplantations induced cell apoptosis by increasing the nuclear translocation of apoptosis-inducing factor; inhibited cell growth and decreased oxidative stress in MCF-7 cells; and increased the cellular susceptibility of both the MCF-7 and MDA-MB-231 cell lines to Doxorubicin and Paclitaxel. Mitochondrial transplantation also consistently decreased Drp-1, which resulted in an enhancement of the tubular mitochondrial network, but a distinct machinery through the increase of parkin and mitochondrial fusion proteins was observed in the Mito and P-Mito groups, respectively. Furthermore, although there were no differences in energy metabolism after transplantation of normal mitochondria, metabolism was switched to the energetic and glycolytic phenotypes when the mitochondria were replaced with dysfunctional mitochondria, namely, Mito8344 and P-Mito8344, due to dramatically induced glycolysis and reduced mitochondrial respiration, respectively. Consequently, transplant-induced growth inhibition was abolished, and cell growth in the Mito8344 group was even higher than that in the control group.ConclusionThis study reveals the antitumour potential of mitochondrial transplantation in breast cancer via distinct regulation of mitochondrial function.
| S-EPMC6343292 | biostudies-literature
Project description:Dipeptidyl peptidase (DPP)-4, a molecular target of DPP-4 inhibitors, which are type 2 diabetes drugs, is expressed in a variety of cell types, tissues and organs. DPP-4 has been shown to be involved in cancer biology, and we have recently shown that a DPP-4 inhibitor promoted the epithelial mesenchymal transition (EMT) in breast cancer cells. The EMT is known to associate with chemotherapy resistance via the induction of ATP-binding cassette (ABC) transporters in cancer cells. Here, we demonstrated that deficiency in DPP-4 promoted chemotherapy resistance via the CXCL12/CXCR4/mTOR axis, activating the TGFβ signaling pathway via the expression of ABC transporters. DPP-4 inhibition enhanced ABC transporters in vivo and in vitro. Doxorubicin (DOX) further induced ABC transporters in DPP-4-deficient 4T1 cells, and the induction of ABC transporters was suppressed by either the CXCR4 inhibitor AMD3100, the mTOR inhibitor rapamycin or a neutralizing TGFβ (1, 2 and 3) antibody(N-TGFβ). Knockdown of snail, an EMT-inducible transcription factor, suppressed ABC transporter levels in DOX-treated DPP-4-deficient 4T1 cells. In an allograft mouse model, however, the effects of DOX in either primary tumor or metastasis were not statistically different between control and DPP-4-kd 4T1. Taken together, our findings suggest that DPP-4 inhibitors potentiate chemotherapy resistance via the induction of ABC transporters by the CXCL12/CXCR4/mTOR/TGFβ signaling pathway in breast cancer cells.
| S-EPMC7037814 | biostudies-literature
Project description:Morphine is an opioid analgesic drug commonly used for pain relief in cancer patients. Here, we report that morphine enhances the mammosphere forming capacity and increases the expression of stemness-related transcription factors Oct4, Sox2 and Nanog. Treatment with morphine leads to enrichment of a side population fraction in MCF-7 cells and the CD44+/CD24(-/low) population in BT549 cells. Consistently, morphine activates Wnt/?-catenin signaling to induce epithelial to mesenchymal transition and promotes metastasis. Moreover, morphine decreases the sensitivity of traditional anti-cancer drugs in breast cancer cells. Nalmefene, an antagonist of morphine, reverses morphine-induced cancer stem cell properties and chemoresistance in breast cancer. In addition, nalmefene abolishes morphine enhancing tumorigenesis in a NOD/SCID mouse model. In conclusion, our findings demonstrate that morphine contributes to chemoresistance via expanding the population of cancer stem cells and promotes tumor growth, thereby revealing a novel role of morphine and providing some new guides in clinical use of morphine.
| S-EPMC4414166 | biostudies-literature
Project description:ObjectiveTo discover the correlated gene with HEATR1 in regulating chemoresistance of gemcitabine.MethodsGene chip analysis was performed to find out differential genes between HEATR1-KD and control groups. The top 20 genes were subjected to high-content screening, and functional assay was implemented. Gene expression profiling was carried out to find the downstream target. Immunohistochemistry and survival analysis were performed.ResultsZNF185 fold change (4.5285) was the most significant between the HEATR1-KD and control groups. Knocking down ZNF185 could promote the chemosensitivity, apoptosis, and proliferative inhibition, with SMAD4 significantly upregulated. Patients with high HEATR1 and SMAD4 or low ZNF185 exhibited better survival.ConclusionHEATR1, ZNF185, and SMAD4 could affect the chemosensitivity of gemcitabine and may be the indicators of gemcitabine selection in the chemotherapy of pancreatic cancer.
| S-EPMC7271247 | biostudies-literature
Project description:Chemoresistance represents a major obstacle to the treatment of human cancers. Increased DNA repair capacity is one of the important mechanisms underlying chemoresistance. In silico analysis indicated that YTHDF1, an m6A binding protein, is a putative tumor promoter in breast cancer. Loss of function studies further showed that YTHDF1 promotes breast cancer cell growth in vitro and in vivo. YTHDF1 facilitates S-phase entry, DNA replication and DNA damage repair, and accordingly YTHDF1 knockdown sensitizes breast cancer cells to Adriamycin and Cisplatin as well as Olaparib, a PARP inhibitor. E2F8 is a target molecule by YTHDF1 which modulates E2F8 mRNA stability and DNA damage repair in a METTL14-dependent manner. These data demonstrate that YTHDF1 has a tumor-promoting role in breast cancer, and is a novel target to overcome chemoresistance.
| S-EPMC8918344 | biostudies-literature
Project description:Activation of oncogenes through DNA amplification/overexpression plays an important role in cancer initiation and progression. Chromosome 17 has many cancer-associated genetic anomalies. This cytogenetic anomaly is strongly associated with poor prognosis of breast cancer. FOXK2 gene is located on 17q25 and encodes a transcriptional factor with a forkhead DNA binding domain. By integrative analysis of public genomic datasets of breast cancers, we found that FOXK2 is frequently amplified and overexpressed in breast cancers. FOXK2 overexpression in breast cancer patients is associated with poor overall survival. FOXK2 knockdown significantly inhibits cell proliferation, invasion and metastasis, and anchorage-independent growth, as well as causes G0/G1 cell cycle arrest in breast cancer cells. Moreover, inhibition of FOXK2 expression sensitizes breast cancer cells to frontline anti-tumor chemotherapies. More importantly, co-overexpression of FOXK2 and PI3KCA with oncogenic mutations (E545K or H1047R) induces cellular transformation in non-tumorigenic MCF10A cells, suggesting that FOXK2 is an oncogene in breast cancer and is involved in PI3KCA-driven tumorigenesis. Our study identified CCNE2, PDK1, and Estrogen receptor alpha (ESR1) as direct transcriptional targets of FOXK2 in MCF-7 cells. Blocking CCNE2- and PDK1-mediated signaling by using small molecule inhibitors has synergistic anti-tumor effects in breast cancer cells. Furthermore, FOXK2 inhibition by gene knockdown or inhibitors for its transcriptional targets (CCNE2 and PDK1) in combination with PI3KCA inhibitor, Alpelisib, showed synergistic anti-tumor effects on breast cancer cells with PI3KCA oncogenic mutations. In summary, we provide compelling evidence that FOXK2 plays an oncogenic role in breast tumorigenesis and targeting FOXK2-mediated pathways may be a potential therapeutic strategy in breast cancer.
| S-EPMC10312425 | biostudies-literature
Project description:Chemoresistance constitutes a major challenge in the treatment of triple-negative breast cancer (TNBC). Mixed-Lineage Kinase 4 (MLK4) is frequently amplified or overexpressed in TNBC where it facilitates the aggressive growth and migratory potential of breast cancer cells. However, the functional role of MLK4 in resistance to chemotherapy has not been investigated so far. Here, we demonstrate that MLK4 promotes TNBC chemoresistance by regulating the pro-survival response to DNA-damaging therapies. We observed that MLK4 knock-down or inhibition sensitized TNBC cell lines to chemotherapeutic agents in vitro. Similarly, MLK4-deficient cells displayed enhanced sensitivity towards doxorubicin treatment in vivo. MLK4 silencing induced persistent DNA damage accumulation and apoptosis in TNBC cells upon treatment with chemotherapeutics. Using phosphoproteomic profiling and reporter assays, we demonstrated that loss of MLK4 reduced phosphorylation of key DNA damage response factors, including ATM and CHK2, and compromised DNA repair via non-homologous end-joining pathway. Moreover, our mRNA-seq analysis revealed that MLK4 is required for DNA damage-induced expression of several NF-кB-associated cytokines, which facilitate TNBC cells survival. Lastly, we found that high MLK4 expression is associated with worse overall survival of TNBC patients receiving anthracycline-based neoadjuvant chemotherapy. Collectively, these results identify a novel function of MLK4 in the regulation of DNA damage response signaling and indicate that inhibition of this kinase could be an effective strategy to overcome TNBC chemoresistance.
| S-EPMC8627512 | biostudies-literature
Project description:Chemoresistance remains a major obstacle to the successful treatment of breast cancer. Especially, more than 80% of cases cannot achieve pathological complete response (pCR) in patients who received neoadjuvant chemotherapy (NAC). Understanding the mechanisms involved in chemoresistance can guide the development of efficient therapies in patients with breast cancer. Herein, we identified a novel p62 isoform with a short 3′UTR (p62-SU, 662-nt) that is associated with chemoresistance by RNA-sequence and verified by qRT-PCR, 3′RACE, and northern blot in breast cancer cells and tissue specimens. Furthermore, enforced expression of p62-SU dramatically promoted the ability of proliferation, migration, invasion, and chemoresistance compared with p62 isoform with a long/full-length 3′UTR (p62-LU, 1485-nt) in vivo and in vitro. Mechanistically, we revealed that CPSF1 could regulate the 3′UTR shorting of p62 by alternative polyadenylation and then enhanced chemoresistance in breast cancer cells. In addition, we found that p62-SU escaped the repression of miR-124-3p and promoted the ability of p62-SU to produce more protein and, subsequently, p62-dependent chemoresistance. Together, our data suggest the p62-SU, generated by CPSF1, plays an essential role in the regulation of breast cancer chemoresistance through CPSF1-p62-miR-124-3p signaling.
2022-03-06 | GSE197894 | GEO