Fatty Acid Synthase Promotes Hepatocellular Carcinoma Growth via S-Phase Kinase-Associated Protein 2/p27 KIP1 Regulation.

Autor:	Cigliano A; Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy.; Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany., Simile MM; Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy., Vidili G; Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy., Pes GM; Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy., Dore MP; Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy., Urigo F; Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy.; Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany., Cossu E; Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany., Che L; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Fracisco, CA 94143, USA., Feo C; Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy., Steinmann SM; Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany., Ribback S; Institute of Pathology, University of Greifswald, 17489 Greifswald, Germany., Pascale RM; Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy., Evert M; Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany., Chen X; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Fracisco, CA 94143, USA.; Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA., Calvisi DF; Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy.
Jazyk:	angličtina
Zdroj:	Medicina (Kaunas, Lithuania) [Medicina (Kaunas)] 2024 Jul 18; Vol. 60 (7). Date of Electronic Publication: 2024 Jul 18.
DOI:	10.3390/medicina60071160
Abstrakt:	Background and Objectives: Aberrant upregulation of fatty acid synthase (FASN), catalyzing de novo synthesis of fatty acids, occurs in various tumor types, including human hepatocellular carcinoma (HCC). Although FASN oncogenic activity seems to reside in its pro-lipogenic function, cumulating evidence suggests that FASN's tumor-supporting role might also be metabolic-independent. Materials and Methods : In the present study, we show that FASN inactivation by specific small interfering RNA (siRNA) promoted the downregulation of the S-phase kinase associated-protein kinase 2 (SKP2) and the consequent induction of p27 KIP1 in HCC cell lines. Results: Expression levels of FASN and SKP2 directly correlated in human HCC specimens and predicted a dismal outcome. In addition, forced overexpression of SKP2 rendered HCC cells resistant to the treatment with the FASN inhibitor C75. Furthermore, FASN deletion was paralleled by SKP2 downregulation and p27 KIP1 induction in the AKT-driven HCC preclinical mouse model. Moreover, forced overexpression of an SKP2 dominant negative form or a p27 KIP1 non-phosphorylatable (p27 KIP1-T187A ) construct completely abolished AKT-dependent hepatocarcinogenesis in vitro and in vivo. Conclusions: In conclusion, the present data indicate that SKP2 is a critical downstream effector of FASN and AKT-dependent hepatocarcinogenesis in liver cancer, envisaging the possibility of effectively targeting FASN-positive liver tumors with SKP2 inhibitors or p27 KIP1 activators.
Databáze:	MEDLINE
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