Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth.
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.
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Surendra K
SK
Shukla
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.|Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Aneesha
A
Dasgupta
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Kamiya
K
Mehla
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Venugopal
V
Gunda
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Enza
E
Vernucci
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Joshua
J
Souchek
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Gennifer
G
Goode
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Ryan
R
King
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Anusha
A
Mishra
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Ibha
I
Rai
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Sangeetha
S
Nagarajan
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Nina V
NV
Chaika
Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Fang
F
Yu
The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.|Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.|Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.|Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Pankaj K
PK
Singh
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002100:Cachexia / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D055442:Metabolome / Q000187:drug effects*; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000975:Antioxidants; D015850:Interleukin-6; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; D012838:Silymarin; D014409:Tumor Necrosis Factor-alpha; D000077385:Silybin
c-Myc; cachexia; cancer metabolism; pancreatic cancer; silibinin