Expression of Fatty Acid Synthase Depends on NAC1 and Is Associated with Recurrent Ovarian Serous Carcinomas

Abstract

Our previous reports demonstrated that NAC1, a BTB/POZ domain-containing nuclear protein, upregulates in recurrent ovarian serous carcinoma and participates in developing drug resistance in cancer cells. The current study applies quantitative proteomics to identify the proteins controlled by NAC1 by comparing the proteomes of SKOV3 cells with and without expression of a dominant negative NAC1 construct, N130. From the proteins that are downregulated by N130 (upregulated by NAC1), we chose to further characterize fatty acid synthase (FASN). Similar to change in protein level, the FASN transcript level in SKOV3 cells was significantly reduced by N130 induction or by NAC1 knockdown. Immunohistochemistry showed that NAC1 and FASN immunointensities in ovarian serous carcinoma tissues had a highly significant correlation (P < .0001). Moreover, we found that recurrent serous carcinomas exhibited higher FASN immunointensities than their matched primary tumors (P < .001). Multivariate analysis showed that an FASN staining score of >1 in serous carcinomas was associated with a worse overall survival time (P < .01). Finally, C93, a new FASN inhibitor, induced massive apoptosis in carboplatin/paclitaxel resistant ovarian cancer cells. In conclusion, we show that NAC1 is essential for FASN expression in ovarian serous carcinomas and the expression of FASN significantly correlates with tumor recurrence and disease aggressiveness. The dependence of drug resistant tumor cells on FASN suggests a potential application of FASN-based therapeutics for recurrent ovarian cancer patients.

Fatty Acid Synthase Is a Potential Therapeutic Target in Estrogen Receptor-/Progesterone Receptor-Positive Endometrioid Endometrial Cancer

“…FASN inhibition has been shown to induce growth inhibition in several human cancer cells [10,12,23]. Our data also show that C75 treatment of endometrioid endometrial cancer cells with positive ER/PR induces growth inhibition.…”

Diagnosis of Serous Tubal Intraepithelial Carcinoma Based on Morphologic and Immunohistochemical Features

“…In our study, we did not include other proteins that have been shown to be present in STICs, nor did we include etiologically important genes and proteins associated with high-grade serous carcinoma, such as p21, p16 cyclin E1, Rsf-1, fatty acid synthase, and laminin C1protein. 1,3,12,14 If they are validated in larger data sets, they may improve the reproducibility of STIC even further.…”

Tumor cell metabolism

“…In contrast, several human cancers, including lung, prostate, ovary, breast, endometrium and colon have often shown FASN overexpression. [78][79][80][81][82][83][84][85][86][87] This overexpression has been shown to participate in very early tumorigenesis, tumor growth and survival. 76,86 FASN upregulation also protects cells from death by inhibiting the intrinsic pathway of apoptosis.…”