Down-regulation of Fatty Acid Synthase Is Associated with Decreased Akt Activation in Lovastatin Induced Apoptosis Cells

YUAN-CHING CHANG^1,2, YEN-HUA HUANG³, CHWEN-MING SHIH³, JUI-YU WU³, CHIEN-LIANG LIU^1,2, SHWU-HUEY WANG⁴ AND CHUN-MAO LIN^3,4*

1. Department of General Surgery, Mackay Memorial Hospital, Taipei City, Taiwan
2. Mackay Medicine, Nursing and Management College, Peito, Taipei City, Taiwan
3. College of Medicine, Taipei Medical University, Taipei City, Taiwan
4. Instrumentation Center, Taipei Medical University, Taipei City, Taiwan

(Received: June 5, 2006; Accepted: July 31, 2006)

ABSTRACT

   Increased fatty acid synthase (FAS) protein expression is coordinated with cancer development.  FAS inhibitors become a focus of anticancer drug development.  Lovastatin, one of the active ingredients in red yeast rice, is a product of Monascus purpureus. Lovastatin has been shown to inhibit proliferation and to induce apoptosis in a variety of tumor cells.  This report shows that chemopreventive effects of lovastatin may be through the down regulation of FAS.  Lovastatin exhibited significant apoptosis-inducing activity in HL-60 cells, as observed by flow cytometry (with 49.83% in sub-G1 peak compared to the control, 10.43%), blebbing cell membrane morphology, and nuclear condensation.  Cellular triglyceride, cholesterol, and free fatty acid in HepG2 cells were reduced to 79%, 81%, and 75%, respectively, upon lovastatin treatment (50 μM) for 4 h.  The relative levels of FAS protein after treatment with 0, 10, 20, and 50 μM lovastatin were 1.00, 0.89, 0.72, and 0.31, respectively.  Phosphorylated Akt was reduced in a dose-dependent manner.  Reverse transcription PCR analysis showed that lovastatin upregulated PPAR-γ and inhibited SREBP-1 mRNA expression in HepG2 cells.  Our current results implicate that lovastatin inhibiting FAS expression is associated with the decreased Akt activation.

Keywords: fatty acid synthase, lovastatin, PKB/Akt, PPAR, statin, SREBP