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Fatty acid synthase overexpression: target for therapy and reversal of chemoresistance in ovarian cancer.

Bauerschlag DO, Maass N, Leonhardt P, Verburg FA, Pecks U, Zeppernick F, Morgenroth A, Mottaghy FM, Tolba R, Meinhold-Heerlein I, Bräutigam K - J Transl Med (2015)

Bottom Line: In most samples, the FASN inhibitor cerulenin markedly decreased FASN expression and cell viability and induced apoptosis.Unlike concomitant administration, sequential cerulenin/cisplatin treatment reduced cisplatin's half maximal inhibitory concentration profoundly (up to 54%) in a cisplatin-resistant cell line, suggesting platinum (re)sensitization.Cisplatin-resistant cells displayed lower (18) F-fluoro-methylcholine uptake than did cisplatin-sensitive cells, suggesting that metabolic imaging might help guide therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Gynecology and Obstetrics, University Medical Center RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. dbauerschlag@ukaachen.de.

ABSTRACT

Background: Fatty acid synthase (FASN) is crucial to de novo long-chain fatty acid synthesis, needed to meet cancer cells' increased demands for membrane, energy, and protein production.

Methods: We investigated FASN overexpression as a therapeutic and chemosensitization target in ovarian cancer tissue, cell lines, and primary cell cultures. FASN expression at mRNA and protein levels was determined by quantitative real-time polymerase chain reaction and immunoblotting and immunohistochemistry, respectively. FASN inhibition's impact on cell viability, apoptosis, and fatty acid metabolism was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide assay, cell death detection enzyme-linked immunosorbent assay, immunoblotting, and (18) F-fluoromethylcholine uptake measurement, respectively.

Results: Relative to that in healthy fallopian tube tissue, tumor tissues had 1.8-fold average FASN protein overexpression; cell lines and primary cultures had 11-fold-100-fold mRNA and protein overexpression. In most samples, the FASN inhibitor cerulenin markedly decreased FASN expression and cell viability and induced apoptosis. Unlike concomitant administration, sequential cerulenin/cisplatin treatment reduced cisplatin's half maximal inhibitory concentration profoundly (up to 54%) in a cisplatin-resistant cell line, suggesting platinum (re)sensitization. Cisplatin-resistant cells displayed lower (18) F-fluoro-methylcholine uptake than did cisplatin-sensitive cells, suggesting that metabolic imaging might help guide therapy.

Conclusions: FASN inhibition induced apoptosis in chemosensitive and platinum-resistant ovarian cancer cells and may reverse cisplatin resistance.

No MeSH data available.


Related in: MedlinePlus

Immunhistochemical analyses of fasn protein expression in patient material. Immunhistochemical analyses of FASN protein expression in a TMA comprising formalin-fixed, paraffin-embedded samples of ovarian cancers of different grades (6 LMP, 9 G1, 42 G2, and 47 G3 tumors) and histological subtypes (serous papillary, mucinous, or endometrioid) from 104 patients versus in 12 healthy fallopian tissue samples. (a) Representative TMA slide immunohistochemically-stained with FASN antibody showed strong FASN expression in ovarian cancer. (b) Statistical evaluation of FASN expression applying the immunoreactive score (IRS), which incorporates protein staining intensity and the percentage of protein-positive cells. Statistically significant FASN overexpression was proven for LMP/G1 tumors or G2/G3 tumors vs. normal tissues (respectively *P < 0.005 and **P < 0.001, U test).
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Fig1: Immunhistochemical analyses of fasn protein expression in patient material. Immunhistochemical analyses of FASN protein expression in a TMA comprising formalin-fixed, paraffin-embedded samples of ovarian cancers of different grades (6 LMP, 9 G1, 42 G2, and 47 G3 tumors) and histological subtypes (serous papillary, mucinous, or endometrioid) from 104 patients versus in 12 healthy fallopian tissue samples. (a) Representative TMA slide immunohistochemically-stained with FASN antibody showed strong FASN expression in ovarian cancer. (b) Statistical evaluation of FASN expression applying the immunoreactive score (IRS), which incorporates protein staining intensity and the percentage of protein-positive cells. Statistically significant FASN overexpression was proven for LMP/G1 tumors or G2/G3 tumors vs. normal tissues (respectively *P < 0.005 and **P < 0.001, U test).

Mentions: As illustrated in Figure 1, strong FASN overexpression was detected in the majority of tumor samples compared to healthy fallopian tube tissue samples. Relative to that in fallopian tube tissue, FASN protein expression – by IRS = immunoreactive scoring - was on average elevated 1.6-fold in LMP/G1 tumor samples and 1.8-fold in G2/G3 tumor samples. The differences with healthy tissue were statistically highly significant (respectively, P = 0.004 and P < 0.001, U test), but FASN expression did not differ between G2/G3 versus LMP/G1 tumor samples (P = 0.169, U test).Figure 1


Fatty acid synthase overexpression: target for therapy and reversal of chemoresistance in ovarian cancer.

Bauerschlag DO, Maass N, Leonhardt P, Verburg FA, Pecks U, Zeppernick F, Morgenroth A, Mottaghy FM, Tolba R, Meinhold-Heerlein I, Bräutigam K - J Transl Med (2015)

Immunhistochemical analyses of fasn protein expression in patient material. Immunhistochemical analyses of FASN protein expression in a TMA comprising formalin-fixed, paraffin-embedded samples of ovarian cancers of different grades (6 LMP, 9 G1, 42 G2, and 47 G3 tumors) and histological subtypes (serous papillary, mucinous, or endometrioid) from 104 patients versus in 12 healthy fallopian tissue samples. (a) Representative TMA slide immunohistochemically-stained with FASN antibody showed strong FASN expression in ovarian cancer. (b) Statistical evaluation of FASN expression applying the immunoreactive score (IRS), which incorporates protein staining intensity and the percentage of protein-positive cells. Statistically significant FASN overexpression was proven for LMP/G1 tumors or G2/G3 tumors vs. normal tissues (respectively *P < 0.005 and **P < 0.001, U test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4504229&req=5

Fig1: Immunhistochemical analyses of fasn protein expression in patient material. Immunhistochemical analyses of FASN protein expression in a TMA comprising formalin-fixed, paraffin-embedded samples of ovarian cancers of different grades (6 LMP, 9 G1, 42 G2, and 47 G3 tumors) and histological subtypes (serous papillary, mucinous, or endometrioid) from 104 patients versus in 12 healthy fallopian tissue samples. (a) Representative TMA slide immunohistochemically-stained with FASN antibody showed strong FASN expression in ovarian cancer. (b) Statistical evaluation of FASN expression applying the immunoreactive score (IRS), which incorporates protein staining intensity and the percentage of protein-positive cells. Statistically significant FASN overexpression was proven for LMP/G1 tumors or G2/G3 tumors vs. normal tissues (respectively *P < 0.005 and **P < 0.001, U test).
Mentions: As illustrated in Figure 1, strong FASN overexpression was detected in the majority of tumor samples compared to healthy fallopian tube tissue samples. Relative to that in fallopian tube tissue, FASN protein expression – by IRS = immunoreactive scoring - was on average elevated 1.6-fold in LMP/G1 tumor samples and 1.8-fold in G2/G3 tumor samples. The differences with healthy tissue were statistically highly significant (respectively, P = 0.004 and P < 0.001, U test), but FASN expression did not differ between G2/G3 versus LMP/G1 tumor samples (P = 0.169, U test).Figure 1

Bottom Line: In most samples, the FASN inhibitor cerulenin markedly decreased FASN expression and cell viability and induced apoptosis.Unlike concomitant administration, sequential cerulenin/cisplatin treatment reduced cisplatin's half maximal inhibitory concentration profoundly (up to 54%) in a cisplatin-resistant cell line, suggesting platinum (re)sensitization.Cisplatin-resistant cells displayed lower (18) F-fluoro-methylcholine uptake than did cisplatin-sensitive cells, suggesting that metabolic imaging might help guide therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Gynecology and Obstetrics, University Medical Center RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. dbauerschlag@ukaachen.de.

ABSTRACT

Background: Fatty acid synthase (FASN) is crucial to de novo long-chain fatty acid synthesis, needed to meet cancer cells' increased demands for membrane, energy, and protein production.

Methods: We investigated FASN overexpression as a therapeutic and chemosensitization target in ovarian cancer tissue, cell lines, and primary cell cultures. FASN expression at mRNA and protein levels was determined by quantitative real-time polymerase chain reaction and immunoblotting and immunohistochemistry, respectively. FASN inhibition's impact on cell viability, apoptosis, and fatty acid metabolism was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide assay, cell death detection enzyme-linked immunosorbent assay, immunoblotting, and (18) F-fluoromethylcholine uptake measurement, respectively.

Results: Relative to that in healthy fallopian tube tissue, tumor tissues had 1.8-fold average FASN protein overexpression; cell lines and primary cultures had 11-fold-100-fold mRNA and protein overexpression. In most samples, the FASN inhibitor cerulenin markedly decreased FASN expression and cell viability and induced apoptosis. Unlike concomitant administration, sequential cerulenin/cisplatin treatment reduced cisplatin's half maximal inhibitory concentration profoundly (up to 54%) in a cisplatin-resistant cell line, suggesting platinum (re)sensitization. Cisplatin-resistant cells displayed lower (18) F-fluoro-methylcholine uptake than did cisplatin-sensitive cells, suggesting that metabolic imaging might help guide therapy.

Conclusions: FASN inhibition induced apoptosis in chemosensitive and platinum-resistant ovarian cancer cells and may reverse cisplatin resistance.

No MeSH data available.


Related in: MedlinePlus