Carnitine palmitoyl transferase-1A (CPT1A): a new tumor specific target in human breast cancer
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Sabina Pucci1,*, Maria Josè Zonetti1, Tommaso Fisco1, Chiara Polidoro1, Gianfranco Bocchinfuso2, Antonio Palleschi2, Giuseppe Novelli1, Luigi G. Spagnoli1, Paola Mazzarelli1,*
1Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy
2Department of Chemical Sciences and Technologies, Tor Vergata University of Rome, Rome, Italy
*These authors have contributed equally to this work
Luigi G. Spagnoli, e-mail: [email protected]
Sabina Pucci, e-mail: [email protected]
Keywords: breast cancer, carnitine palmitoyl transferase-1A, HDAC inhibitor, tumor metabolism, tumor specific target
Received: July 28, 2015 Accepted: January 01, 2016 Published: January 21, 2016
Transcriptional mechanisms epigenetically-regulated in tumoral tissues point out new targets for anti-cancer therapies. Carnitine palmitoyl transferase I (CPT1) is the rate-limiting enzyme in the transport of long-chain fatty acids for β-oxidation. Here we identified the tumor specific nuclear CPT1A as a product of the transcript variant 2, that doesn’t retain the classical transferase activity and is strongly involved in the epigenetic regulation of cancer pro-survival, cell death escaping and tumor invasion pathways. The knockdown of CPT1A variant 2 by small interfering RNAs (siRNAs), was sufficient to induce apoptosis in MCF-7, SK-BR3 and MDA-MB-231 breast cancer cells. The cell death triggered by CPT1A silencing correlated with reduction of HDAC activity and histone hyperacetylation. Docking experiments and molecular dynamics simulations confirmed an high binding affinity of the variant 2 for HDAC1. The CPT1A silenced cells showed an up-regulated transcription of pro-apoptotic genes (BAD, CASP9, COL18A1) and down-modulation of invasion and metastasis related-genes (TIMP-1, PDGF-A, SERPINB2). These findings provide evidence of the CPT1 variant 2 involvement in breast cancer survival, cell death escape and invasion. Thus, we propose nuclear CPT1A as a striking tumor specific target for anticancer therapeutics, more selective and effective as compared with the well-known HDAC inhibitors.
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