Browse
Submit Data
Databases
API
Help

Dataset Information

24 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PGC-1? mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis.

ABSTRACT: Cancer cells can divert metabolites into anabolic pathways to support their rapid proliferation and to accumulate the cellular building blocks required for tumour growth. However, the specific bioenergetic profile of invasive and metastatic cancer cells is unknown. Here we report that migratory/invasive cancer cells specifically favour mitochondrial respiration and increased ATP production. Invasive cancer cells use the transcription coactivator peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PPARGC1A, also known as PGC-1?) to enhance oxidative phosphorylation, mitochondrial biogenesis and the oxygen consumption rate. Clinical analysis of human invasive breast cancers revealed a strong correlation between PGC-1? expression in invasive cancer cells and the formation of distant metastases. Silencing of PGC-1? in cancer cells suspended their invasive potential and attenuated metastasis without affecting proliferation, primary tumour growth or the epithelial-to-mesenchymal program. Inherent genetics of cancer cells can determine the transcriptome framework associated with invasion and metastasis, and mitochondrial biogenesis and respiration induced by PGC-1? are also essential for functional motility of cancer cells and metastasis.

SUBMITTER: LeBleu VS

PROVIDER: S-EPMC4369153 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis

Project description:The study aimed to analyse the transcriptome of mouse cancer cells while in primary tumor, in circulation and after homing to metastatic site. The model used here is the 4T1 cancer cell orthotopic model. GFP-labeled 4T1 breast cancer cells were orthotopically implanted in the mammary pads of mice. In this mouse model for breast cancer, primary breast tumors emerge following injection of cancer cells in the breast pad of female mice and subsequently develop lung metastases with 100% penetrance. Circulating cancer cells (CCC) and cancer cells from the primary tumors (PCC) and metastatic lungs (MCC) were FACS purified and their transcriptome assayed by gene expression microarray. RNA was extracted from PCC, MCC, and CCC using RNeasy Plus Mini Kit (Qiagen) and submitted to the Molecular Genetics Core Facility at Children’s Hospital (Boston, MA). Microarray analysis was performed using Mouse Ref8 Gene Expression BeadChip (Illumina platform).

2014-09-23 | E-GEOD-37344 | biostudies-arrayexpress

PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis

2014-09-23 | GSE37344 | GEO

Lactate promotes metastasis of normoxic colorectal cancer stem cells through PGC-1α-mediated oxidative phosphorylation.

Project description:Uneven oxygen supply in solid tumors leads to hypoxic and normoxic regions. Hypoxic cells exhibit increased secretion of lactate, which creates an acidic tumor microenvironment (TME). This acidic TME is positively associated with tumor metastasis. Despite the increased metastatic capacity of hypoxic cells, they are located relatively further away from the blood vessels and have limited access to the circulatory system. Studies have shown that cancer stem cells (CSCs) are enriched for tumor metastasis-initiating cells and generally undergo aerobic respiration, which could be enhanced by lactate. We therefore hypothesized that TME-derived lactate may promote the metastasis of normoxic CSCs. In the present study, the abundance of hypoxic and normoxic CSCs was analyzed in primary CRC tumors. It was found that the proportion of normoxic CSCs was positively associated with tumor stage. Using two human CRC cell lines, LoVo and SW480, and a patient-derived xenograft (XhCRC), it was found that treatment with lactate promoted normoxic CSC metastasis. Metabolism analysis indicated that, upon treatment with lactate, oxidative phosphorylation (OXPHOS) activity in normoxic CSCs was enhanced, whereas hypoxic CSCs were rarely altered. At the molecular level, the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of lactate oxidation, was found to be elevated in normoxic CSCs. Furthermore, PGC-1α knockdown markedly reduced the metastatic potential of normoxic CSCs. Notably, both the PGC-1α-mediated OXPHOS activity and metastatic potential were impaired when hypoxia-inducible factor-1α (HIF-1α) was activated in normoxic CSCs. Together, these findings provide a therapeutic strategy against tumor metastasis through the targeting of PGC-1α and, thus, the suppression of lactate-feeding OXPHOS in normoxic CSCs may improve the therapeutic benefit of patients with cancer, particularly CRC.

| S-EPMC9329320 | biostudies-literature

PGC-1α induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma.

Project description:IntroductionProgress in the knowledge of metabolic interactions between cancer and its microenvironment is ongoing and may lead to novel therapeutic approaches. Until recently, melanoma was considered a glycolytic tumour due to mutations in mitochondrial-DNA, however, these malignant cells can regain OXPHOS capacity via the transfer of mitochondrial-DNA, a process that supports their proliferation in-vitro and in-vivo. Here we study how melanoma cells acquire mitochondria and how this process is facilitated from the tumour microenvironment.MethodsPrimary melanoma cells, and MSCs derived from patients were obtained. Genes' expression and DNA quantification was analysed using Real-time PCR. MSC migration, melanoma proliferation and tumour volume, in a xenograft subcutaneous mouse model, were monitored through bioluminescent live animal imaging.ResultsHuman melanoma cells attract bone marrow-derived stromal cells (MSCs) to the primary tumour site where they stimulate mitochondrial biogenesis in the MSCs through upregulation of PGC1a. Mitochondria are transferred to the melanoma cells via direct contact with the MSCs. Moreover, inhibition of MSC-derived PGC1a was able to prevent mitochondrial transfer and improve NSG melanoma mouse tumour burden.ConclusionMSC mitochondrial biogenesis stimulated by melanoma cells is prerequisite for mitochondrial transfer and subsequent tumour growth, where targeting this pathway may provide an effective novel therapeutic approach in melanoma.

| S-EPMC9276678 | biostudies-literature

PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity.

Project description:Due to its role in regulation of mitochondrial function, PGC1α is emerging as an important player in ageing and neurodegenerative disorders. PGC1α exerts its neuroprotective effects by promoting mitochondrial biogenesis (MB) and functioning. However, the precise regulatory role of PGC1α in the control of mitochondrial dynamics (MD) and neurotoxicity is still unknown. Here we elucidate the role of PGC1αin vitro and in vivo in the regulatory context of MB and MD in response to lead (II) acetate as a relevant model of neurotoxicity. We show that there is an adaptive response (AR) to lead, orchestrated by the BAP31-calcium signalling system operating between the ER and mitochondria. We find that this hormetic response is controlled by a cell-tolerated increase of PGC1α expression, which in turn induces a balanced expression of fusion/fission genes by binding to their promoters and implying its direct role in regulation of MD. However, dysregulation of PGC1α expression through either stable downregulation or overexpression, renders cells more susceptible to lead insult leading to mitochondrial fragmentation and cell death. Our data provide novel evidence that PGC1α expression is a key regulator of MD and the maintenance of tolerated PGC1α expression may offer a promising strategy for neuroprotective therapies.

| S-EPMC4600622 | biostudies-literature

PGC-1α Controls Mitochondrial Biogenesis in Drug-Resistant Colorectal Cancer Cells by Regulating Endoplasmic Reticulum Stress.

Project description:Anti-cancer drug resistance is a serious issue for patients with colorectal cancer (CRC). Although recent studies have shown the mechanism by which CRC cells become drug resistant, novel strategies for overcoming this drug resistance have not yet been developed. To address this problem, we characterized 5-fluorouracil (5FU)-resistant CRC cells after treatment with 5FU, and focused on the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in these cells. In 5FU-resistant CRC cells, the 5FU did not considerably decrease the mitochondrial biogenesis or mitochondrial complex I and IV activities, and only partially decreased the antioxidant enzymatic activity, oxygen consumption ratio, and cell survival. The expression of PGC-1α was remarkably increased in the 5FU-resistant CRC cells compared with the 5FU-sensitive CRC cells. The 5FU-resistant CRC cells displayed enhanced mitochondrial biogenesis, oxidative phosphorylation, and antioxidant enzyme activities against 5FU-induced reactive oxygen species, because of the increased expression of PGC-1α. PGC-1α inhibited 5FU-induced endoplasmic reticulum (ER) stress in the 5FU-resistant CRC cells, resulting in the suppression of apoptosis. These findings reveal that PGC-1α plays an important role in drug resistance in 5FU-resistant CRC cells. Moreover, PGC-1α could serve as a novel target in patients with 5FU-resistant CRC.

| S-EPMC6480203 | biostudies-literature

Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder.

Project description:Autistic spectrum disorder (ASD) is a neurodevelopmental disorder and has a high prevalence in children. Recently, mitochondrial oxidative stress has been proposed to be associated with ASD. Besides, SIRT1/PGC-1α signaling plays an important role in combating oxidative stress. In this study, we sought to determine the role of SIRT1/PGC-1α signaling in the ASD lymphoblastoid cell lines (LCLs). In this study, the mRNA and protein expressions of SIRT1/PGC-1α axis genes were assessed in 35 children with ASD and 35 healthy controls (matched for age, gender, and IQ). An immortalized LCL was established by transforming lymphocytes with Epstein-Barr virus. Next, we used ASD LCLs and control LCLs to detect SIRT1/PGC-1α axis genes expression and oxidative damage. Finally, the effect of overexpression of PGC-1α on oxidative injury in the ASD LCLs was determined. SIRT1/PGC-1α axis genes expression was downregulated at RNA and protein levels in ASD patients and LCLs. Besides, the translocation of cytochrome c and DIABLO from mitochondria to the cytosol was found in the ASD LCLs. Moreover, the intracellular reactive oxygen species (ROS) and mitochondrial ROS and cell apoptosis were increased in the ASD LCLs. However, overexpression of PGC-1α upregulated the SIRT1/PGC-1α axis genes expression and reduced cytochrome c and DIABLO release in the ASD LCLs. Also, overexpression of PGC-1α reduced the ROS generation and cell apoptosis in the ASD LCLs. Overexpression of PGC-1α could reduce the oxidative injury in the ASD LCLs, and PGC-1α may act as a target for treatment.

| S-EPMC5491272 | biostudies-other

miR449a/SIRT1/PGC-1α Is Necessary for Mitochondrial Biogenesis Induced by T-2 Toxin.

Project description:T-2 toxin is one of the type A trichothecenes produced mainly by the Fusarium genus. Due to its broad distribution and highly toxic nature, it is of great concern as a threat to human health and animal breeding. In addition to its ribotoxic effects, T-2 toxin exposure leads to mitochondrial dysfunction, reactive oxygen species (ROS) accumulation and eventually cell apoptosis. We observed that mitochondrial biogenesis is highly activated in animal cells exposed to T-2 toxin, probably in response to the short-term toxic effects of T-2 toxin. However, the molecular mechanisms of T-2 toxin-induced mitochondrial biogenesis remain unclear. In this study, we investigated the regulatory mechanism of key factors in the ROS production and mitochondrial biogenesis that were elicited by T-2 toxin in HepG2 and HEK293T cells. Low dosages of T-2 toxin significantly increased the levels of both mitochondrial biogenesis and ROS. This increase was linked to the upregulation of SIRT1, which is controlled by miR-449a, whose expression was strongly inhibited by T-2 toxin treatment. In addition, we found that T-2 toxin-induced mitochondrial biogenesis resulted from SIRT1-dependent PGC-1α deacetylation. The accumulation of PGC-1α deacetylation, mediated by high SIRT1 levels in T-2 toxin-treated cells, activated the expression of many genes involved in mitochondrial biogenesis. Together, these data indicated that the miR449a/SIRT1/deacetylated PGC-1α axis plays an essential role in the ability of moderate concentrations of T-2 toxin to stimulate mitochondrial biogenesis and ROS production.

| S-EPMC5760504 | biostudies-literature

PGC-1α promotes mitochondrial respiration and biogenesis during the differentiation of hiPSCs into cardiomyocytes.

Project description:Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are readily available, robustly reproducible, and physiologically appropriate human cells for clinical applications and research in the cardiovascular field, hiPSC-CMs cultured in vitro retain an immature metabolic phenotype that limits their application, and little is known about the underlying molecular mechanism controlling mitochondrial metabolic maturation during human induced pluripotent stem cells (hiPSCs ) differentiation into cardiomyocytes. In this study, we found that peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) played an important role in inducing mitochondrial biogenesis and establishing oxidative phosphorylation (OXPHOS) during the cardiac differentiation of hiPSCs. Knocking down PGC-1α by siRNA impaired mitochondrial respiration, while upregulating PGC-1α by ZLN005 promoted mitochondrial biosynthesis and function by regulating the expression of downstream genes involved in mitochondrial dynamics and oxidative metabolism in hiPSC-CMs. Furthermore, we found that estrogen-related receptor α (ERRα) was required for the induction of PGC-1α stimulatory effects in hiPSC-CMs. These findings provide key insights into the molecular control of mitochondrial metabolism during cardiac differentiation and may be used to generate more metabolically mature cardiomyocytes for application.

| S-EPMC8427271 | biostudies-literature

SIRT1 facilitates hepatocellular carcinoma metastasis by promoting PGC-1?-mediated mitochondrial biogenesis.

Project description:SIRT1 is a multifaceted NAD+-dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a novel mechanism of SIRT1-induced hepatocellular carcinoma (HCC) metastasis. SIRT1 overexpression was frequently detected in human HCC specimens and was associated with microvascular invasion (P = 0.0039), advanced tumor node metastasis (TNM) stages (P = 0.0016), HCC recurrence (P = 0.021) and poor outcomes (P = 0.039). Lentivirus-mediated knockdown of SIRT1 in MHCC97H cells reduced invasion and metastasis in vitro and in vivo. SIRT1 depletion attenuated mitochondrial biogenesis and adenosine triphosphate (ATP) production but did not affect epithelial-mesenchymal transition. Elevated SIRT1 expression strongly correlated with the upregulation of PGC-1? in HCC specimens, and ectopic expression of SIRT1 increased PGC-1? levels. In cell assays and an orthotopic transplantation model, PGC-1? overexpression reversed the inhibitory effects of SIRT1 depletion on invasion and metastasis by enhancing mitochondrial biogenesis. These findings reveal the involvement of SIRT1 in HCC metastasis and provide a rationale for exploring therapeutic targets against the SIRT1/PGC-1? axis.

| S-EPMC5045394 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data