title: Pioglitazone, an anti-diabetic drug requires sustained MAPK activation for its anti-tumor activity in MCF7 breast cancer cells, independent of PPAR-γ pathway.
abstract: BACKGROUND
  The thiazolidinedione (TZD) class of peroxisome proliferator-activated receptor gamma (PPAR-γ) ligands are known for their ability to induce adipocyte differentiation, to increase insulin sensitivity including anticancer properties. But, whether or not upstream events like MAPK activation or PPAR-γ signaling are involved or associated with this anticancer activity is not well understood in breast cancer cells. The role of MAPK and PPAR pathways during the pioglitazone (Pio) induced PPAR-γ independent anticancer activity in MCF7 cells has been focused here.
  
  
  METHODS
  The anticancer activity of Pio has been investigated in breast cancer cells in vitro. Anti-tumor effects were assessed by alamar blue assay, Western blot analysis, cell cycle analysis, and annexin V-FITC/PI binding assay by flow cytometry, Hoechst staining and luciferase assay.
  
  
  RESULTS
  The anticancer activity of Pio is found to be correlating with the up regulation of CDKIs (p21/p27) and down regulation of CDK-4. This study demonstrates that the induction of CDKIs by Pio is due to the sustained activation of MAPK. The Pio-mediated activation of MAPK is transmitted to activate ELK-1 and the related anti-proliferation is blocked by MEK inhibitor (PD-184352).
  
  
  CONCLUSIONS
  Pio suppresses the proliferation of MCF7 cells, at least partly by a PPAR-γ-independent mechanism involving the induction of p21 which in turn requires sustained activation of MAPK. These findings implicate the utility of Pio in the treatment of PPAR positive or negative human cancers and the development of a new class of compounds to enhance the effectiveness of Pio.
authors.affiliation: Discovery Research SBU, Dr. Reddy's Laboratories Ltd., Hyderabad, India.
authors.forename: Labanyamoy
authors.initials: L
authors.lastname: Kole
authors.affiliation: Experimental Medicine & Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Kolkata, India.
authors.forename: Mrinmoy
authors.initials: M
authors.lastname: Sarkar
authors.affiliation: Experimental Medicine & Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Kolkata, India.
authors.forename: Anwesha
authors.initials: A
authors.lastname: Deb
authors.affiliation: Experimental Medicine & Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Kolkata, India. Electronic address: bgiri.emscrl@gmail.com.
authors.forename: Biplab
authors.initials: B
authors.lastname: Giri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000077205:Pioglitazone; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D020928:Mitogen-Activated Protein Kinases; D000077205:Pioglitazone
keywords: CDKI; MAPK; MCF7; PPAR-γ; Pioglitazone