title: Mycophenolic acid induces adipocyte-like differentiation and reversal of malignancy of breast cancer cells partly through PPARγ.
abstract: Mycophenolic acid (MPA) has been known for decades to be an anticancer and immunosuppressive agent and has significant anticancer properties, but its underlying molecular mechanisms are poorly characterized. Peroxisome proliferator-activated receptor gamma (PPARγ) has a central role in adipocyte differentiation, and MPA has been shown to be a potent PPARγ agonist. Whether PPARγ activation has a putative role in the anticancer efficacy of MPA via induction of adipocyte-like differentiation has not been elucidated. In the present study, MPA was demonstrated to dose-dependently activate PPARγ transcription in the GAL4-hPPARγ (LBD) chimeric receptor assay and PPRE-luc reporter gene assay with an EC(50) of 5.2-9.3 μM. Treatment of the breast cancer cell lines MDA-MB-231 and MCF-7 with MPA resulted in differentiation of adipose tissue that was characterized by accumulation of intracellular lipids, enlargement of cell volume, and permanent withdrawal from the cell cycle at the G1/G0 stage. At a molecular level, the expression of three adipocyte differentiation markers (PPARγ, adipsin D, and aP2) was remarkably induced in differentiated breast cancer cells. However, RNA interference experiments showed that PPARγ-knockdown cannot completely reverse the differentiated state of MDA-MB-231 cells after MPA treatment. These data suggest that the effects of MPA on adipocyte-like terminal differentiation of breast cancer cells are (at least in part) due to PPARγ activation, which is a novel anticancer mechanism of MPA.
authors.affiliation: College of Life Science, Hebei Normal University, Shijiazhuang, China.
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Zheng
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Lu
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiao-Xi
authors.initials: XX
authors.lastname: Shui
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: He
authors.forename: Qin
authors.initials: Q
authors.lastname: Jiang
authors.forename: Bao-Hua
authors.initials: BH
authors.lastname: Zhao
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Si
mesh_terms: D017667:Adipocytes / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D016466:CHO Cells; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D016193:G1 Phase / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D009173:Mycophenolic Acid / Q000494:pharmacology*; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D047495:PPAR gamma; D009173:Mycophenolic Acid