Pioglitazone inhibits cancer cell growth through STAT3 inhibition and enhanced AIF expression via a PPARγ‐independent pathway

Tsubaki, Masanobu; Takeda, Tomoya; Tomonari, Yoshika; Kawashima, Keishi; Itoh, Tatsuki; Imano, Motohiro; Satou, Takao; Nishida, Shozo

doi:10.1002/jcp.26225

Cited by 27 publications

(16 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other evidences showed that troglitazone induces apoptosis of lung cancer cell line NCI-H23 via a mitochondrial pathway through the activation of ERK1/2 [12]. In addition to anti-proliferative effects, TZD can sensitize cancer cells to anticancer therapies enhancing the cytotoxic effect of cisplatin and oxaliplatin by suppressing survivin and increasing the apoptosis-inducing factor (AIF) expression [20]. Among TZDs, pioglitazone was approved for the treatment of type 2 diabetes and continues to be recommended in current guidelines since pioglitazone bladder cancer concerns have been largely attenuated by recent evidences [21].…”

Section: Discussionmentioning

confidence: 99%

Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC

Ciaramella

Sasso

Liello

et al. 2019

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background: Pioglitazone, a synthetic peroxisome proliferator activated receptor (PPAR-γ) ligand, is known as an antidiabetic drug included in the thiazolidinediones (TZDs) class. It regulates the lipid and glucose cell metabolism and recently a role in the inhibition of numerous cancer cell processes has been described. Methods: In our work we investigate the anti-tumor effects of pioglitazone in in vitro models of non small cell lung cancer (NSCLC) and also, we generated ex-vivo three-dimensional (3D) cultures from human lung adenocarcinoma (ADK) as a model to test drug efficacy observed in vitro. The inhibitory effect of pioglitazone on cell proliferation, apoptosis and cell invasion in a panel of human NSCLC cell lines was evaluated by multiple assays. Results: Pioglitazone reduced proliferative and invasive abilities with an IC 50 ranging between 5 and 10 μM and induced apoptosis of NSCLC cells. mRNA microarray expression profiling showed a down regulation of MAPK, Myc and Ras genes after treatment with pioglitazone; altered gene expression was confirmed by protein analysis in a dose-related reduction of survivin and phosphorylated proteins levels of MAPK pathway. Interestingly mRNA microarray analysis showed also that pioglitazone affects TGFβ pathway, which is important in the epithelial-tomesenchimal transition (EMT) process, by down-regulating TGFβR1 and SMAD3 mRNA expression. In addition, extracellular acidification rate (ECAR) and a proportional reduction of markers of altered glucose metabolism in treated cells demonstrated also cell bioenergetics modulation by pioglitazone. Conclusions: Data indicate that PPAR-γ agonists represent an attractive treatment tool and by suppression of cell growth (in vitro and ex vivo models) and of invasion via blockade of MAPK cascade and TGFβ/SMADs signaling, respectively, and its role in cancer bioenergetics and metabolism indicate that PPAR-γ agonists represent an attractive treatment tool for NSCLC.

show abstract

Section: Discussionmentioning

confidence: 99%

Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC

Ciaramella

Sasso

Liello

et al. 2019

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…Thus, PPAR control may have significant promise for breast cancer prevention. Recently, PPAR ligands were shown to inhibit the growth of a variety of transformed cells (9,12,13); hence signals that modulate PPAR activity may serve a primary role in regulating breast cancer metastasis and may be major targets for treatment of breast cancer.…”

Section: Introductionmentioning

confidence: 99%

15d-PGJ₂ inhibits NF-κB and AP-1-mediated MMP-9 expression and invasion of breast cancer cell by means of a heme oxygenase-1-dependent mechanism

et al. 2020

View full text Add to dashboard Cite

Activation of peroxisome proliferator-activated receptor  (PPAR) serves as a key factor in the proliferation and invasion of breast cancer cells and is a potential therapeutic target for breast cancer. However, the mechanisms underlying this effect remain largely unknown. Heme oxygenase-1 (HO-1) is induced and overexpressed in various cancers and is associated with features of tumor aggressiveness. Recent studies have shown that HO-1 is a major downstream target of PPAR. In this study, we investigated the effects of induction of HO-1 by PPAR on TPAinduced MMP-9 expression and cell invasion using MCF-7 breast cancer cells. TPA treatment increased NF-B /AP-1 DNA binding as well as MMP-9 expression. These effects were significantly blocked by 15d-PGJ2, a natural PPAR ligand. 15d-PGJ2 induced HO-1 expression in a dose-dependent manner. Interestingly, HO-1 siRNA significantly attenuated the inhibition of TPA-induced MMP-9 protein expression and cell invasion by 15d-PGJ2. These results suggest that 15d-PGJ2 inhibits TPA-induced MMP-9 expression and invasion of MCF-7 cells by means of a heme oxygenase-1-dependent mechanism. Therefore, PPAR/HO-1 signaling-pathway inhibition may be beneficial for prevention and treatment of breast cancer. [BMB Reports 2020; 53(4): 212-217]

show abstract

“…However, there are conflicting reports of caspase involvement in apoptosis induced by PPARγ agonists in cancer cells. Pioglitazone-mediated apoptosis occurs via a caspase-independent pathway in bladder cancer cells ( 5 ). In contrast, pretreatment of PC-3 cells with z-VAD-fmk inhibited PPARγ agonist-mediated apoptosis, indicating the involvement of the caspase-dependent pathway in prostate cancer ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone mediates apoptosis in Caki cells via downregulating c‑FLIP_(L) expression and reducing Bcl‑2 protein stability

et al. 2021

View full text Add to dashboard Cite

Pioglitazone is an anti-diabetic agent used in the treatment of type 2 diabetes, which belongs to the thiazolidinediones (TZDs) group. TZDs target peroxisome proliferator-activated receptor γ (PPARγ), which functions as a transcription factor of the nuclear hormone receptor. Pioglitazone has antitumor effects in several cancer types and could be a tool for drug therapy in various cancer treatments. Nevertheless, the molecular basis for pioglitazone-induced anticancer effects in renal cancer (RC) has not yet been elucidated. Thus, the aim of the present study was to investigate the detailed signaling pathway underlying pioglitazone-induced apoptosis in Caki cells derived from human clear cell renal cell carcinoma. As a result, it was demonstrated by flow cytometry analysis and Annexin V-propidium iodide staining that pioglitazone treatment induced apoptotic cell death in a dose-dependent manner in Caki cells. The protein expression levels of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) (L) and Bcl-2, which were determined by western blotting, decreased after pioglitazone treatment in Caki cells. Flow cytometry and western blot analyses demonstrated that pioglitazone-mediated apoptosis was blocked following pretreatment with the pan-caspase inhibitor, z-VAD-fmk, indicating that pioglitazone-induced apoptosis was mediated via a caspase-dependent signaling pathway. However, the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC), did not affect pioglitazone-mediated apoptosis and degradation of c-FLIP (L) and Bcl-2 protein. Of note, it was found by western blot analysis that Bcl-2 protein expression was downregulated by the decreased protein stability of Bcl-2 in pioglitazone-treated Caki cells. In conclusion, these findings indicated that pioglitazone-induced apoptosis is regulated through caspase-mediated degradation of FLIP (L) and reduction of Bcl-2 protein stability, suggesting that pioglitazone is a feasible apoptotic agent that could be used in the treatment of human RC.

show abstract

Pioglitazone inhibits cancer cell growth through STAT3 inhibition and enhanced AIF expression via a PPARγ‐independent pathway

Cited by 27 publications

References 26 publications

Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC

Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC

15d-PGJ₂ inhibits NF-κB and AP-1-mediated MMP-9 expression and invasion of breast cancer cell by means of a heme oxygenase-1-dependent mechanism

Pioglitazone mediates apoptosis in Caki cells via downregulating c‑FLIP_(L) expression and reducing Bcl‑2 protein stability

Contact Info

Product

Resources

About

Pioglitazone inhibits cancer cell growth through STAT3 inhibition and enhanced AIF expression via a PPARγ‐independent pathway

Cited by 27 publications

References 26 publications

Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC

Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC

15d-PGJ2 inhibits NF-κB and AP-1-mediated MMP-9 expression and invasion of breast cancer cell by means of a heme oxygenase-1-dependent mechanism

Pioglitazone mediates apoptosis in Caki cells via downregulating c‑FLIP(L) expression and reducing Bcl‑2 protein stability

Contact Info

Product

Resources

About

15d-PGJ₂ inhibits NF-κB and AP-1-mediated MMP-9 expression and invasion of breast cancer cell by means of a heme oxygenase-1-dependent mechanism

Pioglitazone mediates apoptosis in Caki cells via downregulating c‑FLIP_(L) expression and reducing Bcl‑2 protein stability