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Guggulsterone decreases proliferation and metastatic behavior of pancreatic cancer cells by modulating JAK/STAT and Src/FAK signaling.

Abstract
Inadequate efficacy, high toxicity and drug resistance associated with existing chemotherapeutic agents mandate a need for novel therapeutic strategies for highly aggressive Pancreatic Cancer (PC). Guggulsterone (GS) exhibits potent anti-proliferative effects against various cancer cells and has emerged as an attractive candidate for use in complementary or preventive cancer therapies. However, the knowledge regarding the therapeutic potential of GS in PC is still limited and needs to be explored. We studied the effect of GS on PC cell growth, motility and invasion and elucidated the molecular mechanisms associated with its anti-tumor effects. Treatment of Capan1 and CD18/HPAF PC cells with GS resulted in dose- and time-dependent growth inhibition and decreased colony formation. Further, GS treatment induced apoptosis and cell cycle arrest as assessed by Annexin-V assay and FACS analysis. Increased apoptosis following GS treatment was accompanied with Bad dephosphorylation and its translocation to the mitochondria, increased Caspase-3 activation, decreased Cyclin D1, Bcl-2 and xIAP expression. Additionally, GS treatment decreased motility and invasion of PC cells by disrupting cytoskeletal organization, inhibiting activation of FAK and Src signaling and decreased MMP9 expression. More importantly, GS treatment decreased mucin MUC4 expression in Capan1 and CD18/HPAF cells through transcriptional regulation by inhibiting Jak/STAT pathway. In conclusion, our results support the utility of GS as a potential therapeutic agent for lethal PC.
AuthorsMuzafar A Macha, Satyanarayana Rachagani, Suprit Gupta, Priya Pai, Moorthy P Ponnusamy, Surinder K Batra, Maneesh Jain
JournalCancer letters (Cancer Lett) Vol. 341 Issue 2 Pg. 166-77 (Dec 01 2013) ISSN: 1872-7980 [Electronic] Ireland
PMID23920124 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Cell Cycle Proteins
  • Isoenzymes
  • MUC4 protein, human
  • Mucin-4
  • Pregnenediones
  • STAT Transcription Factors
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • pregna-4,17-diene-3,16-dione
  • Focal Adhesion Kinase 1
  • Janus Kinases
  • PTK2 protein, human
  • src-Family Kinases
Topics
  • Apoptosis (drug effects)
  • Cell Cycle Proteins (genetics, metabolism)
  • Cell Line, Tumor
  • Cell Movement (drug effects)
  • Cell Proliferation (drug effects)
  • Cytoskeleton (drug effects, metabolism)
  • Dose-Response Relationship, Drug
  • Focal Adhesion Kinase 1 (genetics, metabolism)
  • Humans
  • Immunoblotting
  • Isoenzymes (genetics, metabolism)
  • Janus Kinases (genetics, metabolism)
  • Microscopy, Confocal
  • Mucin-4 (genetics, metabolism)
  • Neoplasm Metastasis
  • Pancreatic Neoplasms (genetics, metabolism, pathology)
  • Pregnenediones (pharmacology)
  • Promoter Regions, Genetic (genetics)
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT Transcription Factors (genetics, metabolism)
  • STAT1 Transcription Factor (genetics, metabolism)
  • STAT3 Transcription Factor (genetics, metabolism)
  • Signal Transduction (drug effects)
  • Time Factors
  • src-Family Kinases (genetics, metabolism)

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