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. 2011 Jan 1;2(1):89-98.

Role of fatty acid synthase in gemcitabine and radiation resistance of pancreatic cancers

Youyun Yang  1 , Hailan Liu, Zhaomin Li, Zijin Zhao, Michelle Yip-Schneider, Qipeng Fan, C Max Schmidt, E Gabriela Chiorean, Jingwu Xie, Liang Cheng, Jey-Hsin Chen, Jian-Ting Zhang
Affiliations

Role of fatty acid synthase in gemcitabine and radiation resistance of pancreatic cancers

Youyun Yang et al. Int J Biochem Mol Biol. .

Abstract

Human fatty acid synthase (FASN) is a homo-dimeric protein with multi-enzymatic activity responsible for the synthesis of palmitate. FASN expression has been found to be up-regulated in multiple types of human cancers and its expression correlates with poor prognosis possibly by causing treatment resistance. In this study, we tested if FASN expression is up-regulated in human pancreatic cancers and if its higher expression level in pancreatic cancers causes intrinsic resistance to gemcitabine and radiation. We found that FASN expression is significantly up-regulated in human pancreatic cancer tissues without any correlation to age, sex, race, and tumor stage. Knocking down or over-expressing FASN significantly down- or up-regulate resistance of pancreatic cancer cell lines to both gemcitabine and radiation treatments. These findings imply that the elevated FASN expression in pancreatic cancers may contribute to unsuccessful treatments of pancreatic cancers by causing intrinsic resistance to both chemotherapy and radiation therapy.

Keywords: Human fatty acid synthase (FASN); gemcitabine; palmitate; pancreatic cancers; radiation treatments; treatment resistance.

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Figures

Figure 1.
Figure 1.
FASN expression in pancreatic ductal adenocarcinoma. Examples of pancreatic normal (A) and cancer (B) tissues on TMA slides were stained by FASN antibody followed by visualization under microscope (20X and 200X magnification were used for the entire core and inset, respectively). Panel C shows the correlation of FASN expression level determined using two different scoring systems. Score 1=semi quantitative scores; Score 2=quantitative imager analysis.
Figure 2.
Figure 2.
Comparison of FASN expression between matched normal and cancer pancreatic tissues. A. FASN expression in pancreatic tissues. Lysates from fresh frozen matching human normal (N) and pancreatic ductal adenocarcinoma (C) tissues were separated by SDS-PAGE followed by Western blot analysis of FASN and actin loading control. B. Quantitation of relative FASN level. The relative FASN level in each sample was measured and normalized to that of actin with the level of FASN in each normal tissue set to 1. The relative levels of FASN in normal and cancer tissues were graphed with the median level in each group marked by (-). Each tissue was marked by the identification number. Statistical analysis was done using Student T-test.
Figure 3.
Figure 3.
Correlation between FASN expression and gemcitabine resistance. A. FASN expression level in Panc-1, MiaPaCa-2, and BxPc-3 cells. Lysates from Panc-1, MiaPaCa-2, and BxPc-3 cells were prepared for Western blot analyses of FASN and actin loading control. B. IC50 of gemcitabine. The effect of anticancer drug gemcitabine on the survival of Panc-1, Mia-PaCa-2, and BxPc-3 cells was determined using MTT assay and IC50 was determined using Prism program. C. 14-3-3σ expression level in Panc-1 and MiaPaCa-2 cells. Lysates from Panc-1 and MiaPaCa-2 cells were prepared for Western blot analyses of 14-3-3σ and GAPDH loading control.
Figure 4.
Figure 4.
Effect of FASN knockdown on gemcitabine response. A. Western blot analysis of FASN following siRNA transfection. Panc-1 cells were transiently transfected with FASN or scrambled control siRNA followed by Western blot analysis of FASN. B. MTT assay. Panc-1 cells transiently transfected with FASN (Si) or scrambled control (Scr) siRNAs were treated with various concentrations of gemcitabine followed by analysis using MTT assy. C. Relative resistance factor. Relative resistance factor (RRF) was derived as described in Materials and Methods. ** p<0.01.
Figure 5.
Figure 5.
Effect of orlistat on gemcitabine response. A. Cytotoxicity of orlistat. Panc-1 cells were treated with different concentrations of orlistat followed by MTT assay. B. Sensitization of gemcitabine resistance by orlistate. Panc-1 cells were treated with different concentrations of gemcitaibne in the absence or presence of 25 μM orlistate followed by MTT assay. C. Relative resistance factor. Relative resistance factor (RRF) to gemcitabine was derived as described in Materials and Methods. ** p<0.01.
Figure 6.
Figure 6.
Effect of FASN over-expression on gemcitabine response. A. FASN expression level. Lysates were prepared from Panc-1 cells with stable trans-fection with FASN cDNA (FASN3 and FASN7) or vector (Vec) control and used for Western blot analysis of FASN and actin loading control. B. Survival assay. Panc-1 stable clones were treated with various concentrations of gemcitabine followed by analysis using MTT assy. C. Relative resistance factor. Relative resistance factor (RRF) to gemcitabine was derived as described in Materials and Methods. ** p<0.01.
Figure 7.
Figure 7.
Effect of FASN over-expression on radiation response. A. Survival assay. Panc-1 cells with stable transfection with FASN cDNA (FASN3 and FASN7) or vector (Vec) control were treated with different doses of γ-irradiation followed by analysis using MTT assy. B. Relative resistance factor. Relative resistance factor (RRF) to γ-irradiation was derived as described in Materials and Methods. ** p<0.01.
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References

    1. Alo PL, Amini M, Piro F, Pizzuti L, Sebastiani V, Botti C, Murari R, Zotti G, Di Tondo U. Immu-nohistochemical expression and prognostic significance of fatty acid synthase in pancreatic carcinoma. Anticancer Res. 2007;27:2523–2527. - PubMed
    1. Witkiewicz AK, Nguyen KH, Dasgupta A, Kennedy EP, Yeo CJ, Lisanti MP, Brody JR. Co-expression of fatty acid synthase and caveolin-1 in pancreatic ductal adenocarcinoma: implications for tumor progression and clinical outcome. Cell Cycle. 2008;7:3021–3025. - PubMed
    1. Liu H, Liu JY, Wu X, Zhang JT. Biochemistry, molecular biology, and pharmacology of fatty acid synthase, an emerging therapeutic target and diagnosis/prognosis marker. Int J Biochem Mol Biol. 2010;1:69–89. - PMC - PubMed
    1. Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci U S A. 1994;91:6379–6383. - PMC - PubMed
    1. Shurbaji MS, Kalbfleisch JH, Thurmond TS. Immunohistochemical detection of a fatty acid synthase (OA-519) as a predictor of progression of prostate cancer. Hum Pathol. 1996;27:917–921. - PubMed

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