Increased Fatty Acid Synthase Is a Therapeutic Target in Multiple Myeloma.

Abstract

Multiple myeloma is a malignancy arising from postgerminal nature B cells. The estimated incidence of multiple myeloma accounts for 10% of hematological malignancies and 1% of all malignancies. Despite therapeutic advance, the disease is essentially incurable. Fatty acid synthase (FAS), the principle enzyme in the endogenous synthsis of fatty acid, is highly expressed in a wide variety of human malignancies and their presursor lesions, including carcinoma of the colon, prostate, ovary, endometrium and breast. One therapeutic target that has not previously been considered for multiple myeloma treatment is the pathway of the endogenous synthesis of fatty acid. For this purpose, we first evaluated a series of human multiple myeloma cases, bone marrow samples for FAS expression by immunohistochemistry, then established FAS mRNA and protein expression in multiple myeloma cell lines and human multiple myeloma plasma cells by RT-PCR and immunoblot analysis. Our results showed that 19 of the 27(70.37%) MM cases were scored as FAS positive by immunohistochemistry, whereas 8 of the 27 (29.64%) were scored negative. FAS mRNA was highly expressed in U266, RPMI8226 cells and 22 of the 27 MM patients, but wasn't detected in healthy donor PBMNCs by RT-PCR. Immunoblot analysis found that FAS protein was detected in 16 of the 27 patients(59.25%) and two above myeloma cell lines but not detected in healthy donor PBMNCs. Encouraged by these findings that human multiple myeloma bone marrow samples and cell lines overexpress FAS, we treated human multiple myeloma cell lines (U266, RPMI8226) in vitro with cerulenin, a native inhibitor of FAS. Cells proliferation was measured by methyl thiazolyl tetrazolium(MTT) analysis and apoptosis was evaluated by flow cytometry. Treat with 5ug/ml—640ug/ml of cerelenin for 24h, the proliferation of U266 cells was obviously inhibited with dosage related effect. The inhibition rate of human skin fibroblast cells are all lower than 30%. When U266 cells are treated for 12h with 20ug/ml of cerulenin, the early stage apoptosis rate revealed by Annxin V/PI using FCM are 56,9%. Our findings suggest that FAS may be an effective target for pharmacological therapy in human multiple myeloma.