Silibinin-Mediated Metabolic Reprogramming Attenuates Pancreatic Cancer-Induced Cachexia and Tumor Growth
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// Surendra K. Shukla 1 , Aneesha Dasgupta 1, 2 , Kamiya Mehla 1 , Venugopal Gunda 1 , Enza Vernucci 1 , Joshua Souchek 1 , Gennifer Goode 1 , Ryan King 1 , Anusha Mishra 1 , Ibha Rai 1 , Sangeetha Nagarajan 1 , Nina V. Chaika 1 , Fang Yu 3 , Pankaj K. Singh 1, 2, 4, 5 1 The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA 2 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA 3 Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA 4 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA 5 Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA Correspondence to: Pankaj K. Singh, e-mail: pankaj.singh@unmc.edu Keywords: pancreatic cancer, cancer metabolism, silibinin, cachexia, c-Myc Received: August 19, 2015 Accepted: September 25, 2015 Published: October 16, 2015 ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models.
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Silibinin increases protein content and decreases MuRF1 and MAFbx expression in skeletal muscle of pancreatic cancer NCr-nu/nu mice.
“Shukla et al. provided compelling evidence that silibinin increases the protein content and decreases MuRF1 and MAFbx expression in skeletal muscle of pancreatic cancer NCr-nu/nu mice [120].”
From Nutraceuticals in the Prevention and Treatment of the Muscle Atrophy (2021) · cites this paper as [120]
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Nutraceuticals in the Prevention and Treatment of the Muscle Atrophy
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- Authors
- Shukla, S. K., Dasgupta, A., Mehla, K., Gunda, V., Vernucci, E., Souchek, J., Goode, G., King, R., Mishra, A., Rai, I., Nagarajan, S., Chaika, N. V., Yu, F., & Singh, P. K.
- Affiliations
- University of Nebraska Medical Center (US)
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2015-10-16
- Volume
- 6
- Issue
- 38
- Pages
- 41146-41161
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC4747396
- OpenAlex
- W1851711468
- Cited by
- 96
- References
- 56
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 9 · 2022: 9 · 2021: 9 · 2020: 29 · 2019: 9 · 2018: 7 · 2017: 6 · 2016: 2 · 2014: 1
- FWCI
- 3.96
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DigitalCommons@UNMC (submittedVersion, cc-by)
- Funders
- American Association for Cancer Research (30-20-25-SING)
- Pancreatic Cancer Action Network (30-20-25-SING, 2P50 CA127297)
- National Institutes of Health (CA163120, CA127297)
- National Cancer Institute (U54CA163120, R01CA163649, CA127297, CA163649, CA 163120, P50CA127297)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Silymarin and Mushroom Poisoning
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- pancreatic ductal adenocarcinoma, cancer cachexia, metabolic reprogramming, c-Myc, STAT3 signaling, glycolysis, tumor growth, natural products, metabolomics, tumor microenvironment, autophagy, oxidative stress, cell cycle arrest, cell invasion, angiogenesis, metastasis, drug resistance, drug repurposing
- MeSH terms
- Silybin, Animals, Antioxidants, Cachexia, Cell Line, Dose-Response Relationship, Drug, Female, Glycolysis, Humans, Mice, Nude, Pancreatic Neoplasms, Silymarin, Tumor Necrosis Factor-alpha, Immunoblotting, Signal Transduction, Interleukin-6, Proto-Oncogene Proteins c-myc, Reverse Transcriptase Polymerase Chain Reaction, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Burden, Cell Proliferation, STAT3 Transcription Factor, Metabolome
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