Silibinin inhibits endometrial carcinoma via blocking pathways of STAT3 activation and SREBP1-mediated lipid accumulation

Shi, Zhengzheng; Zhou, Qing; Gao, Shuhong; Li, Wenzhi; Li, Xin; Liu, Zhiming; Jin, Pengpeng; Jiang, Jie

doi:10.1016/j.lfs.2018.11.037

Cited by 41 publications

(18 citation statements)

References 33 publications

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“…We show here that FASN endogenous levels are upregulated during senescence in mouse and human cells. Numerous evidence suggest that cancer cells have deregulated lipid metabolism (de novo FAS and β-oxidation pathway) 41–43 , which resemble our findings.…”

Section: Discussionsupporting

confidence: 89%

FASN activity is important for the initial stages of the induction of senescence

et al. 2019

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Senescent cells accumulate in several tissues during ageing and contribute to several pathological processes such as ageing and cancer. Senescence induction is a complex process not well defined yet and is characterized by a series of molecular changes acquired after an initial growth arrest. We found that fatty acid synthase (FASN) levels increase during the induction of senescence in mouse hepatic stellate cells and human primary fibroblasts. Importantly, we also observed a significant increase in FASN levels during ageing in mouse liver tissues. To probe the central role of FASN in senescence induction, we used a small-molecule inhibitor of FASN activity, C75. We found that C75 treatment prevented the induction of senescence in mouse and human senescent cells. Importantly, C75 also reduced the expression of the signature SASP factors interleukin 1α (IL-1α), IL-1β and IL-6, and suppressed the secretion of small extracellular vesicles. These findings were confirmed using a shRNA targeting FASN. In addition, we find that FASN inhibition induces metabolic changes in senescent cells. Our work underscores the importance of C75 as a pharmacological inhibitor for reducing the impact of senescent cell accumulation.

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Section: Discussionsupporting

confidence: 89%

FASN activity is important for the initial stages of the induction of senescence

et al. 2019

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“…As a key transcription factor in lipid metabolism, SREBP1 has been thoroughly studied, yet it still needs to be elucidated how it functions in cancer. SREBP1 is a cancer-promoting gene in colorectal cancer, prostate cancer, breast cancer, endometrial carcinoma and nasopharyngeal carcinoma [28, 34, 35, 38]. Previously, we demonstrated that by suppressing PC stemness, SREBP1 acts as an effective chemotherapy sensitizer [30].…”

Section: Discussionmentioning

confidence: 99%

High glucose microenvironment accelerates tumor growth via SREBP1-autophagy axis in pancreatic cancer

Zhou

Qian

et al. 2019

J Exp Clin Cancer Res

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Background Diabetes is recognized to be a risk factor of pancreatic cancer, but the mechanism has not been fully elucidated. Sterol regulatory element binding protein 1 (SREBP1) is an important transcription factor involved in both lipid metabolism and tumor progression. However, the relationship between high glucose microenvironment, SREBP1 and pancreatic cancer remains to be explored. Methods Clinical data and surgical specimens were collected. Pancreatic cancer cell lines BxPc-3 and MiaPaCa-2 were cultured in specified medium. Immunohistochemistry (IHC) and western blotting were performed to detect the expression of SREBP1. MTT and colony formation assays were applied to investigate cell proliferation. Immunofluorescence, mRFP-GFP adenoviral vector and transmission electron microscopy were performed to evaluate autophagy. We used streptozotocin (STZ) to establish a high glucose mouse model for the in vivo study. Results We found that high blood glucose levels were associated with poor prognosis in pancreatic cancer patients. SREBP1 was overexpressed in both pancreatic cancer tissues and pancreatic cancer cell lines. High glucose microenvironment promoted tumor proliferation, suppressed apoptosis and inhibited autophagy level by enhancing SREBP1 expression. In addition, activation of autophagy accelerated SREBP1 expression and suppressed apoptosis. Moreover, high glucose promotes tumor growth in vivo by enhancing SREBP1 expression. Conclusion Our results indicate that SREBP1-autophagy axis plays a crucial role in tumor progression induced by high glucose microenvironment. SREBP1 may represent a novel target for pancreatic cancer prevention and treatment.

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“…Investigations into the molecular mechanisms involved in the antioxidant, immunomodulatory, antifibrotic, anticancer, and antiviral activities of silibinin have consistently suggested its ability to function as a natural down-modulator of the signal transducer and activator of transcription (STAT3) [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Using computational and experimental approaches, we recently delineated the molecular bases of the silibinin-STAT3 interaction.…”

Section: Silibinin: From An Old Remedy To a Direct Stat3 Inhibitormentioning

confidence: 99%

Silibinin and SARS-CoV-2: Dual Targeting of Host Cytokine Storm and Virus Replication Machinery for Clinical Management of COVID-19 Patients

Bosch-Barrera

Martín-Castillo

Buxó

et al. 2020

JCM

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COVID-19, the illness caused by infection with the novel coronavirus SARS-CoV-2, is a rapidly spreading global pandemic in urgent need of effective treatments. Here we present a comprehensive examination of the host- and virus-targeted functions of the flavonolignan silibinin, a potential drug candidate against COVID-19/SARS-CoV-2. As a direct inhibitor of STAT3—a master checkpoint regulator of inflammatory cytokine signaling and immune response—silibinin might be expected to phenotypically integrate the mechanisms of action of IL-6-targeted monoclonal antibodies and pan-JAK1/2 inhibitors to limit the cytokine storm and T-cell lymphopenia in the clinical setting of severe COVID-19. As a computationally predicted, remdesivir-like inhibitor of RNA-dependent RNA polymerase (RdRp)—the central component of the replication/transcription machinery of SARS-CoV-2—silibinin is expected to reduce viral load and impede delayed interferon responses. The dual ability of silibinin to target both the host cytokine storm and the virus replication machinery provides a strong rationale for the clinical testing of silibinin against the COVID-19 global public health emergency. A randomized, open-label, phase II multicentric clinical trial (SIL-COVID19) will evaluate the therapeutic efficacy of silibinin in the prevention of acute respiratory distress syndrome in moderate-to-severe COVID-19-positive onco-hematological patients at the Catalan Institute of Oncology in Catalonia, Spain.

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Silibinin inhibits endometrial carcinoma via blocking pathways of STAT3 activation and SREBP1-mediated lipid accumulation

Cited by 41 publications

References 33 publications

FASN activity is important for the initial stages of the induction of senescence

FASN activity is important for the initial stages of the induction of senescence

High glucose microenvironment accelerates tumor growth via SREBP1-autophagy axis in pancreatic cancer

Silibinin and SARS-CoV-2: Dual Targeting of Host Cytokine Storm and Virus Replication Machinery for Clinical Management of COVID-19 Patients

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