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Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer.

ABSTRACT: Despite major advances in early detection and prognosis, chemotherapy resistance is a major hurdle in the battle against breast cancer. Identifying predictive markers and understanding the mechanisms are key steps to overcoming chemoresistance. Methylation-controlled J protein (MCJ, also known as DNAJC15) is a negative regulator of mitochondrial respiration and has been associated with chemotherapeutic drug sensitivity in cancer cell lines. Here we show, in a retrospective study of a large cohort of breast cancer patients, that low MCJ expression in breast tumors predicts high risk of relapse in patients treated with chemotherapy; however, MCJ expression does not correlate with response to endocrine therapy. In a prospective study in breast cancer patients undergoing neoadjuvant therapy, low MCJ expression also correlates with poor clinical response to chemotherapy and decreased disease-free survival. Using MCJ-deficient mice, we demonstrate that lack of MCJ is sufficient to induce mammary tumor chemoresistance in vivo. Thus, loss of expression of this endogenous mitochondrial modulator in breast cancer promotes the development of chemoresistance.

SUBMITTER: Fernandez-Cabezudo MJ

PROVIDER: S-EPMC4888911 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer.

Fernández-Cabezudo Maria J MJ Faour Issam I Jones Kenneth K Champagne Devin P DP Jaloudi Mohammed A MA Mohamed Yassir A YA Bashir Ghada G Almarzooqi Saeeda S Albawardi Alia A Hashim M Jawad MJ Roberts Thomas S TS El-Salhat Haytham H El-Taji Hakam H Kassis Adnan A O'Sullivan Dylan E DE Christensen Brock C BC DeGregori James J Al-Ramadi Basel K BK Rincon Mercedes M

JCI insight 20160501 7

Despite major advances in early detection and prognosis, chemotherapy resistance is a major hurdle in the battle against breast cancer. Identifying predictive markers and understanding the mechanisms are key steps to overcoming chemoresistance. Methylation-controlled J protein (MCJ, also known as DNAJC15) is a negative regulator of mitochondrial respiration and has been associated with chemotherapeutic drug sensitivity in cancer cell lines. Here we show, in a retrospective study of a large cohor ...[more]

PMID: 27275014

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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.

Project description:BackgroundClaudin-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.MethodsWe 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.ResultsSilencing 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.ConclusionHigh 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.

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Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer.

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Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer.

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