Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth

Shukla, Surendra K.; Dasgupta, Aneesha; Mehla, Kamiya; Gunda, Venugopal; Vernucci, Enza; Souchek, Joshua J.; Goode, Gennifer D.; King, Ryan J.; Mishra, Anusha; Rai, Ibha; Sangeetha, N.; Chaika, Nina V.; Yu, Fang; Singh, Pankaj K.

doi:10.18632/oncotarget.5843

Cited by 77 publications

(70 citation statements)

References 53 publications

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“…Cell cycle analysis was performed by staining the cells with Telford reagent as described previously (22). Caspase 3/7 activity was determined by Promega Caspase-Glo kit (Madison, WI, USA) as described previously (23, 24). …”

Section: Methodsmentioning

confidence: 99%

De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

et al. 2017

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Pancreatic adenocarcinoma is moderately responsive to gemcitabine-based chemotherapy, the most widely used single agent therapy for pancreatic cancer. While the prognosis in pancreatic cancer remains grim in part due to poor response to therapy, previous attempts at identifying and targeting the resistance mechanisms have not been very successful. By leveraging TCGA dataset, we identified lipid metabolism as the metabolic pathway that most significantly correlated with poor gemcitabine response in pancreatic cancer patients. Furthermore, we investigated the relationship between alterations in lipogenesis pathway and gemcitabine resistance by utilizing tissues from the genetically engineered mouse model and human pancreatic cancer patients. We observed a significant increase in fatty acid synthase (FASN) expression with increasing disease progression in spontaneous pancreatic cancer mouse model, and a correlation of high FASN expression with poor survival in patients and poor gemcitabine responsiveness in cell lines. We observed a synergistic effect of FASN inhibitors with gemcitabine in pancreatic cancer cells in culture and orthotopic implantation models. Combination of gemcitabine and the FASN inhibitor orlistat significantly diminished stemness, in part due to induction of ER stress that resulted in apoptosis. Moreover, direct induction of ER stress with thapsigargin caused a similar decrease in stemness and showed synergistic activity with gemcitabine. Our in vivo studies with orthotopic implantation models demonstrated a robust increase in gemcitabine responsiveness upon inhibition of fatty acid biosynthesis with orlistat. Altogether, we demonstrate that fatty acid biosynthesis pathway manipulation can help overcome the gemcitabine resistance in pancreatic cancer by regulating ER stress and stemness.

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Section: Methodsmentioning

confidence: 99%

De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

et al. 2017

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“…RNA isolation and quantitative RT-PCR Total RNA was extracted from cells or tissue lysates by using TRIzol reagent (Invitrogen) as previously discussed (Shukla et al, 2015). cDNA was synthesized using Verso-cDNA synthesis kit (Thermo Fisher Scientific) according to the manufacturer's protocol.…”

Section: Cell Viability Assaysmentioning

confidence: 99%

“…Caspase 3/7 activity assay C2C12 myotubes were treated with control or cancer cell CM. Caspase 3/7 activity assay was performed using Promega Caspase Glo-kit as previously described (Shukla et al, 2015).…”

Section: Immunoblottingmentioning

confidence: 99%

SIRT1–NOX4 signaling axis regulates cancer cachexia

Dasgupta

Shukla

Vernucci

et al. 2020

Journal of Experimental Medicine

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Approximately one third of cancer patients die due to complexities related to cachexia. However, the mechanisms of cachexia and the potential therapeutic interventions remain poorly studied. We observed a significant positive correlation between SIRT1 expression and muscle fiber cross-sectional area in pancreatic cancer patients. Rescuing Sirt1 expression by exogenous expression or pharmacological agents reverted cancer cell–induced myotube wasting in culture conditions and mouse models. RNA-seq and follow-up analyses showed cancer cell–mediated SIRT1 loss induced NF-κB signaling in cachectic muscles that enhanced the expression of FOXO transcription factors and NADPH oxidase 4 (Nox4), a key regulator of reactive oxygen species production. Additionally, we observed a negative correlation between NOX4 expression and skeletal muscle fiber cross-sectional area in pancreatic cancer patients. Knocking out Nox4 in skeletal muscles or pharmacological blockade of Nox4 activity abrogated tumor-induced cachexia in mice. Thus, we conclude that targeting the Sirt1–Nox4 axis in muscles is an effective therapeutic intervention for mitigating pancreatic cancer–induced cachexia.

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“…Silibinin has been ascribed anticancer potential because of its manifold inhibitory effects on tumor growth in various cancer cells. Using cultured cells and animal models, Shukla et al showed that silibinin induces metabolic reprogramming, which diminishes the growth and cachectic properties of pancreatic cancer cells [31]. Momeny et al showed the potential anti-cancer activity of silibinin to inhibit the proliferative and invasive characteristics of the epithelial ovarian cancer cells that show an autocrine heregulin/human epidermal growth factor receptor 3 (HRG/HER3) pathway [32].…”

Section: Discussionmentioning

confidence: 99%

Silibinin Inhibits Platelet-Derived Growth Factor-Driven Cell Proliferation via Downregulation of N-Glycosylation in Human Tenon's Fibroblasts in a Proteasome-Dependent Manner

Chen

et al. 2016

PLoS ONE

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The objective of this study was to evaluate the effects of silibinin on cell proliferation in platelet-derived growth factor (PDGF)-treated human Tenon's fibroblasts (HTFs). The effect of silibinin on cell proliferation in PDGF-treated HTFs was determined by examining the expression of proliferating cell nuclear antigen (PCNA) and performing WST-1 assays. Cell cycle progression was evaluated using flow cytometry. The related cyclins and cyclin-dependent kinases (CDKs) were also analyzed using western blot. A modified rat trabeculectomy model was established to evaluate the effect of silibinin on cell proliferation in vivo. Western blot analysis was carried out to determine the effect of silibinin on the expression of PDGF receptor and on the downstream signaling pathways regulated by PDGF receptor. PDGF elevated the expression of PCNA in HTFs, and this elevation was inhibited by silibinin. The inhibitory effect of silibinin on cell proliferation was also confirmed via WST-1 assay. PDGF-stimulated cell cycle in HTFs was delayed by silibinin, and the related cyclin D1 and CDK4 were also suppressed by silibinin. In the rat model of trabeculectomy, silibinin reduced the expression of PCNA at the site of blebs in vivo. The effects of silibinin on PDGF-stimulated HTFs were mediated via the downregulation of PDGF receptor-regulated signaling pathways, such as ERKs and STATs, which may be partially caused by the downregulation of N-glycosylation of PDGF receptor beta (PDGFRβ). The effect of silibinin on modulation of N-glycosylation of PDGFRβ was mediated in a proteasome-dependent manner. Silibinin inhibited cell proliferation and delayed cell cycle progression in PDGF-treated HTFs in vitro. PDGF also modulated the process of N-glycosylation of the PDGFRβ in a proteasome-dependent manner. Our findings suggest that silibinin has potential therapeutic applications in glaucoma filtering surgery.

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Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth

Cited by 77 publications

References 53 publications

De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

SIRT1–NOX4 signaling axis regulates cancer cachexia

Silibinin Inhibits Platelet-Derived Growth Factor-Driven Cell Proliferation via Downregulation of N-Glycosylation in Human Tenon's Fibroblasts in a Proteasome-Dependent Manner

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