Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-Troglitazone-induced Apoptosis in Prostate Cancer Cells Involve AMP-activated Protein Kinase

Santha, Sreevidya; Viswakarma, Navin; Das, Subhasis; Rana, Ajay; Rana, Basabi

doi:10.1074/jbc.m115.663526

Cited by 20 publications

(19 citation statements)

References 51 publications

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“…The effect of PPAR-γ ligands on cell growth inhibition and apoptosis has been investigated in various cancers 47 . Recent research has showed that knockdown of PPAR-γ expression reduces the cleavage of caspase 3 during the early stages of apoptosis 48 . Moreover, studies have documented that PPAR-γ activation might be a promising target for osteosarcoma.…”

Section: Discussionmentioning

confidence: 99%

Oridonin exerts anticancer effect on osteosarcoma by activating PPAR-γ and inhibiting Nrf2 pathway

et al. 2018

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Osteosarcoma is the most common high-grade human primary malignant bone sarcoma with lower survival in the past decades. Oridonin, a bioactive diterpenoid isolated from Rabdosia rubescens, has been proved to possess potent anti-cancer effects. However, its potential mechanism still remains not fully clear nowadays. In this study, we investigated the anticancer effect of oridonin on human osteosarcoma and illuminated the underlying mechanisms. In vitro, oridonin inhibited the cell viability of various osteosarcoma cells. We demonstrated that oridonin induced mitochondrial-mediated apoptosis by increasing Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (MMP), triggering reactive oxygen species (ROS) generation and activating caspase-3 and caspase-9 cleavage in MG-63 and HOS cells. Moreover, we found that oridonin triggered ROS by inhibiting NF-E2-related factor 2 (Nrf2) pathway and induced mitochondrial apoptosis via inhibiting nuclear factor-κB (NF-κB) activation by activating Peroxisome Proliferator-Activated Receptor γ (PPAR-γ) in MG-63 and HOS cells. We further confirmed the results by PPAR-γ inhibitor GW9662, PPAR-γ siRNA as well as overexpression of PPAR-γ and Nrf2 in vitro. Furthermore, our in vivo study showed that oridonin inhibited tumor growth with high safety via inducing apoptosis through activating PPAR-γ and inhibiting Nrf2 activation in xenograft model inoculated HOS tumor. Taken together, oridonin exerted a dramatic pro-apoptotic effect by activating PPAR-γ and inhibiting Nrf2 pathway in vitro and in vivo. Therefore, oridonin may be a promising and effective agent for human osteosarcoma in the future clinical applications.

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Section: Discussionmentioning

confidence: 99%

Oridonin exerts anticancer effect on osteosarcoma by activating PPAR-γ and inhibiting Nrf2 pathway

et al. 2018

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“…It has also been reported that the AMPK‐activators may work well in combination with chemotherapy, indicating that AMPK activity is associated with antitumor efficacy. Recently, biguanides, the first line pharmacotherapy for glucose control, appeared to activate AMPK and improve response to chemotherapy by removing cancer stem cell in a variety of cancers: Also, thiazolidinediones (TZDs), a class of insulin‐sensitizing drugs, activate AMPK both directly and indirectly via the induction of adiponectin, leading to tumor suppression . Due to these findings, according to http://clinicaltrials.gov (https://clinicaltrials.gov/ct2/home), there are currently many trials of biguanides or TZDs for cancer mainly in combination with chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, biguanides, the first line pharmacotherapy for glucose control, appeared to activate AMPK 7 and improve response to chemotherapy by removing cancer stem cell in a variety of cancers 39,40 : Also, thiazolidinediones (TZDs), a class of insulin-sensitizing drugs, activate AMPK both directly and indirectly via the induction of adiponectin, leading to tumor suppression. 41,42 Due to these findings, according to ClinicalTrials.gov (https://clinicaltrials.gov/ct2/ home), there are currently many trials of biguanides or TZDs for cancer mainly in combination with chemotherapy. As for predicting the effect of these drugs, AMPK pathway-related SNPs may be promising markers.…”

Section: Discussionmentioning

confidence: 99%

AMPK variant, a candidate of novel predictor for chemotherapy in metastatic colorectal cancer: A meta‐analysis using TRIBE, MAVERICC and FIRE3

Tokunaga

Cao

Naseem

et al. 2019

Intl Journal of Cancer

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AMP‐activated protein kinase (AMPK) is a key sensor of energy homeostasis and regulates cell metabolism, proliferation and chemotherapy/radiotherapy sensitivities. This study aimed to explore the relationship between the AMPK pathway‐related single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with metastatic colorectal cancer (mCRC). We analyzed a total of 884 patients with mCRC enrolled in three randomized clinical trials (TRIBE, MAVERICC and FIRE‐3: where patients were treated with FOLFIRI, mFOLFOX6 or FOLFOXIRI combined with bevacizumab or cetuximab as the first‐line chemotherapy). The association between AMPK pathway‐related SNPs and clinical outcomes was analyzed across the six treatment cohorts, using a meta‐analysis approach. Our meta‐analysis showed that AMPK pathway had significant associations with progression‐free survival (PFS; p < 0.001) and overall survival (OS; p < 0.001), but not with tumor response (TR; p = 0.220): PRKAA1 rs13361707 was significantly associated with favorable PFS (log HR = −0.219, SE = 0.073, p = 0.003), as well as PRKAA1 rs10074991 (log HR = −0.215, SE = 0.073, p = 0.003), and there were suggestive associations of PRKAG1 rs1138908 with unfavorable OS (log HR = 0.170, SE = 0.083, p = 0.041), and of UBE2O rs3803739 with unfavorable PFS (log HR = 0.137, SE = 0.068, p = 0.042) and OS (log HR = 0.210, SE = 0.077, p = 0.006), although these results were not significant after false discovery rate adjustment. AMPK pathway‐related SNPs may be predictors for chemotherapy in mCRC. Upon validation, our findings would provide novel insight for selecting treatment strategies.

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“…This pathway is stimulated during late-stage prostate cancer and may represent an essential survival mechanism [16][17][18][19]. Activated AMPK induces autophagy, promotes mitochondrial biogenesis and is involved in apoptosis [18,20,21], thereby fostering prostate cancer growth and survival, whereas silencing AMPK expression reduces prostate cancer cell proliferation and migration [13,22]. However, other studies report that AMPK has a tumor suppressor role in prostate cancer [19,[23][24][25], so that potent and selective chemical probes [26] will be essential to understand the enigmatic function of AMPK in cancer and other pathologies [2,3,9,12].…”

Section: Introductionmentioning

confidence: 99%

The Potent and Selective AMPK Inhibitor BAY-3827 Shows Strong Efficacy in Androgen-Dependent Prostate Cancer Models

Lemos

Schulze

Baumgart

et al. 2020

Preprint

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Background: 5´ adenosine monophosphate-activated kinase (AMPK) is an essential regulator of cellular energy homeostasis which has been associated with different pathologies, including cancer. Precisely defining the role of AMPK in these processes necessitates the availability of a potent and selective inhibitor.Methods: High-throughput screening and subsequent chemical optimization led to the identification of the selective inhibitor BAY-3827. Cell proliferation and mechanistic assays, as well as gene expression analysis and chromatin immunoprecipitation were used to investigate the cellular impact of BAY-3827 and the crosstalk between lipid metabolism and androgen signaling in prostate cancer models. Also, fatty acid turnover was determined by examining lipid droplet formation.Results: BAY-3827 prevented phosphorylation of acetyl-CoA carboxylase 1 and showed strongest anti-proliferative activity in androgen-dependent prostate cancer cell lines. Analysis of genes involved in AMPK signaling revealed that the expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), fatty acid synthase (FASN) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), all of which are involved in lipid metabolism, was strongly upregulated by androgen in responsive prostate cancer cell lines. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) analysis identified androgen receptor (AR) binding peaks in these genes. BAY-3827 strongly down-regulated the expression of lipase E (LIPE), cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B) and serine-threonine kinase AKT3 in the responsive prostate cancer cell lines. Also, the expression of members of the carnitine palmitoyl-transferase 1 (CPT1) family was inhibited by BAY-3827, and this was paralleled by impaired lipid flux.Conclusions: The availability of the potent and selective inhibitor BAY-3827 will contribute to a better understanding of the biological role of AMPK signaling in cancer, especially in prostate adenocarcinoma.

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Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-Troglitazone-induced Apoptosis in Prostate Cancer Cells Involve AMP-activated Protein Kinase

Cited by 20 publications

References 51 publications

Oridonin exerts anticancer effect on osteosarcoma by activating PPAR-γ and inhibiting Nrf2 pathway

Oridonin exerts anticancer effect on osteosarcoma by activating PPAR-γ and inhibiting Nrf2 pathway

AMPK variant, a candidate of novel predictor for chemotherapy in metastatic colorectal cancer: A meta‐analysis using TRIBE, MAVERICC and FIRE3

The Potent and Selective AMPK Inhibitor BAY-3827 Shows Strong Efficacy in Androgen-Dependent Prostate Cancer Models

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