Inhibition of peroxisome proliferator‐activated receptor γ activity suppresses pancreatic cancer cell motility

Nakajima, Atsushi; Tomimoto, Ayako; Fujita, Koji; Sugiyama, Michiko; Ikeda, Ikuko; Hosono, Kunihiro; Endo, Hideki; Yoneda, Kyoko; Iida, Hiroshi; Inamori, Masahiko; Kubota, Kensuke; Saito, Satoru; Nakajima, N.; Wada, Koichiro; Nagashima, Yoji; Nakagama, Hitoshi

doi:10.1111/j.1349-7006.2008.00904.x

Cited by 32 publications

(32 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, we noted higher PPAR-γ expression in GBM cells, which could contribute to their rapid proliferation. Consistent with this, a previous study found that PPAR-γ activation induced tumor formation and reduced the overall survival time in pancreatic cancer (32). GBM cells have highlevel of LDH as glycolytic enzyme and SDH as enzyme for TCA cycle compared to NB cells.…”

Section: Discussionsupporting

confidence: 79%

High-capacity glycolytic and mitochondrial oxidative metabolisms mediate the growth ability of glioblastoma

Kim

Han

Jang

et al. 2015

International Journal of Oncology

View full text Add to dashboard Cite

Abstract. Among the primary brain tumors, glioblastoma multiforme (GBM) has a radical proliferation ability that complicates the therapeutic modulation of cancer progression. The majority of GBM patients have a low survival rate (<1 year) due to radical tumor growth and late cancer diagnosis. Previous reports have shown that astrocytes have a specific metabolic organization that includes the production of lactate, the storage of glycogen, and use of lactate to support neurons which possess higher capacity of metabolism compared to neurons. We hypothesized that these characteristics of astrocytes could contribute to enhanced proliferation of GBM compared to neuroblastoma (NB). Here, we show that U87MG cells (a model of GBM) proliferate more rapidly than SH-SY5Y cells (a model of NB). A higher extracellular acidification rate and maximal mitochondrial oxygen consumption rate were observed in U87MG cells compared to SH-SY5Y cells. The expression levels of lactate dehydrogenase (LDH)-A and LDH-B were higher in U87MG cells and primary cultured astrocytes than in SH-SY5Y cells and neurons. Furthermore, the mRNA levels of succinate dehydrogenase and peroxisome proliferator-activated receptor-γ were high in U87MG cells, suggesting that these cells have high capacity for mitochondrial metabolism and uptake of fatty acids related to synthesis of the cell membrane, respectively. Taken together, we demonstrate that GBM cells are characterized by activation of the LDH-expression-related glycolytic pathway and mitochondrial metabolic capacity, suggesting two innate properties of astrocytes that could provide a driving force for the growth ability of GBM. Based on these findings, we propose that therapeutic approaches aimed at treating GBM could target LDH for modulating the metabolic properties of GBM cells.

show abstract

Section: Discussionsupporting

confidence: 79%

High-capacity glycolytic and mitochondrial oxidative metabolisms mediate the growth ability of glioblastoma

Kim

Han

Jang

et al. 2015

International Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…Therefore, we posited that MKK4 functions as a tumor suppressor in lung adenocarcinomas driven by mutant Kras and Tp53 and tested this hypothesis in mice. The findings reported here support this hypothesis and revealed that MKK4 functions as a tumor suppressor partly by decreasing levels of peroxisomal proliferatoractivated receptor ␥ (PPAR␥), a nuclear receptor for fatty acids and eicosanoids that plays divergent roles in different tumor models (31,32,37,41,42). S-Label; MP Biomedicals) for 45 min.…”

Section: Figsupporting

confidence: 68%

“…7B). One of the genes with the most prominently increased (5.0-fold) expression was PPAR␥, a transcription factor that functions as a nuclear receptor for fatty acids and eicosanoids and can reportedly promote or inhibit tumorigenesis (31,32,37,41,42). Pparg encodes two protein isoforms (␥1 and ␥2), the mRNA levels of which increased 1.5-and 6.3-fold, respectively, following MKK4 knockdown in 393P cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Some of these genes play critical roles in the extracellular matrix (Bgn and Vcam1), lymphangiogenesis (Vegfc), inflammation and response to inflammatory cytokines (Il13ra1, Csf1, Ccr9, Cxcl11, and Cxcl7), transcriptional regulation (Satb1, Smarca2, and Id2), cell polarity (Inadl, Crb3, and Pard6b), and epithelium-to-mesenchyme transition (Ncam1, Vim, and Snail1). Although many of these genes could have contributed to the enhanced invasive and metastatic activity, we chose to investigate the role of PPAR␥, owing to the degree to which its expression increased in MKK4-deficient cells and its reported role in other tumor models (7,27,37,41). We found that PPAR␥ promoted tumor cell invasion and increased in abundance through an MKK4 kinase-dependent pathway that did not involve canonical MKK4 substrates.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Map2k4 Functions as a Tumor Suppressor in Lung Adenocarcinoma and Inhibits Tumor Cell Invasion by Decreasing Peroxisome Proliferator-Activated Receptor γ2 Expression

Ahn

Yang

Gibbons

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

MAP2K4 encodes a dual-specificity kinase (mitogen-activated protein kinase kinase 4, or MKK4) that is mutated in a variety of human malignancies, but the biochemical properties of the mutant kinases and their roles in tumorigenesis have not been fully elucidated. Here we showed that 8 out of 11 cancer-associated MAP2K4 mutations reduce MKK4 protein stability or impair its kinase activity. On the basis of findings from bioinformatic studies on human cancer cell lines with homozygous MAP2K4 loss, we posited that MKK4 functions as a tumor suppressor in lung adenocarcinomas that develop in mice owing to expression of mutant Kras and Tp53. Conditional Map2k4 inactivation in the bronchial epithelium of mice had no discernible effect alone but increased the multiplicity and accelerated the growth of incipient lung neoplasias induced by oncogenic Kras. MKK4 suppressed the invasion and metastasis of Kras-Tp53-mutant lung adenocarcinoma cells. MKK4 deficiency increased peroxisomal proliferator-activated receptor ␥2 (PPAR␥2) expression through noncanonical MKK4 substrates, and PPAR␥2 enhanced tumor cell invasion. We conclude that Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing PPAR␥2 levels.

show abstract

“…PPAR-c is a nuclear receptor serving as a transcription factor to control cell differentiation, apoptosis and glucose metabolism (Kliewer and Wilson 1998). Ligands for PPAR-c such as anti-diabetic drugs of the thiazolidinedione (TDD) class pioglitazone, troglitazone and rosiglitazone (Cho and Momose 2008;Krentz et al 2008) exert anti-inflammatory effects and reduce PC growth in experimental models (Nakajima et al 2008;Dong et al 2009). The antiinflammatory effects associate with suppression of COX-2 and NF-jB activities, evidencing complex intracellular pathways and their suppression of tumor growth partially occurs via reducing VEGF (Dong et al 2009).…”

Section: Ppar-c Ligands: General and Pancreas Cancer-specific Anti-tumentioning

confidence: 98%

A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme

Elmacı

Altinöz²

2016

Biochem Genet

View full text Add to dashboard Cite

Pancreatic cancer (PC) and glioblastoma multiforme (GBM) are among the human cancers with worst prognosis which require an urgent need for efficient therapies. Here, we propose to apply to treat both malignancies with a triple combination of drugs, which are already in use for different indications. Recent studies demonstrated a considerable link between risk of PC and diabetes. In experimental models, anti-diabetogenic agents suppress growth of PC, including metformin (M), pioglitazone (P) and lithium (L). L is used in psychiatric practice, yet also bears anti-diabetic potential and selectively inhibits glycogen synthase kinase-3 beta (GSK-3β). M, a biguanide class anti-diabetic agent shows anticancer activity via activating AMP-activated protein kinase (AMPK). Glitazones bind to PPAR-γ and inhibit NF-κB, triggering cell proliferation, apoptosis resistance and synthesis of inflammatory cytokines in cancer cells. Inhibition of inflammatory cytokines could simultaneously decrease tumor growth and alleviate cancer cachexia, having a major role in PC mortality. Furthermore, mutual synergistic interactions exist between PPAR-γ and GSK-3β, between AMPK and GSK-3β and between AMPK and PPAR-γ. In GBM, M blocks angiogenesis and migration in experimental models. Very noteworthy, among GBM patients with type 2 diabetes, usage of M significantly correlates with better survival while reverse is true for sulfonylureas. In experimental models, P synergies with ligands of RAR, RXR and statins in reducing growth of GBM. Further, usage of P was found to be lesser in anaplastic astrocytoma and GBM patients, indicating a protective effect of P against high-grade gliomas. L is accumulated in GBM cells faster and higher than in neuroblastoma cells, and its levels further increase with chronic exposure. Recent studies revealed anti-invasive potential of L in GBM cell lines. Here, we propose that a triple-agent regime including drugs already in clinical usage may provide a metabolic adjuvant therapy for PC and GBM.

show abstract

Inhibition of peroxisome proliferator‐activated receptor γ activity suppresses pancreatic cancer cell motility

Cited by 32 publications

References 30 publications

High-capacity glycolytic and mitochondrial oxidative metabolisms mediate the growth ability of glioblastoma

High-capacity glycolytic and mitochondrial oxidative metabolisms mediate the growth ability of glioblastoma

Map2k4 Functions as a Tumor Suppressor in Lung Adenocarcinoma and Inhibits Tumor Cell Invasion by Decreasing Peroxisome Proliferator-Activated Receptor γ2 Expression

A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme

Contact Info

Product

Resources

About