1. ¹Istituto Superiore di Sanità, Rome, Italy
2. ²Medical Oncology Unit, Catholic University, Rome, Italy
3. ³Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, Italy
4. ⁴CNR Institute of Molecular Biology and Pathology, Rome, Italy
5. ⁵CNR Institute of Neurobiology and Molecular Medicine, Rome, Italy
6. ⁶Department of Experimental Medicine and Biochemical Sciences, University 'Tor Vergata', Rome, Italy

Correspondence: C Spadafora, Biology and Animal Sciences, Istituto Superiore di Sanità (Italian National Health Insitute), Viale Regina Elena 299, Via del Castro Laurenziano 25, Rome 00161, Italy. E-mail: cspadaf@tin.it

⁷These authors contributed equally to this work

⁸Current address: Clinical Oncology, Department of Internal Medicine, University of Foggia, Italy

Received 15 October 2004; Revised 21 December 2004; Accepted 27 January 2005; Published online 4 April 2005.

Abstract

Undifferentiated cells and embryos express high levels of endogenous non-telomerase reverse transcriptase (RT) of retroposon/retroviral origin. We previously found that RT inhibitors modulate cell growth and differentiation in several cell lines. We have now sought to establish whether high levels of RT activity are directly linked to cell transformation. To address this possibility, we have employed two different approaches to inhibit RT activity in melanoma and prostate carcinoma cell lines: pharmacological inhibition by two characterized RT inhibitors, nevirapine and efavirenz, and downregulation of expression of RT-encoding LINE-1 elements by RNA interference (RNAi). Both treatments reduced proliferation, induced morphological differentiation and reprogrammed gene expression. These features are reversible upon discontinuation of the anti-RT treatment, suggesting that RT contributes to an epigenetic level of control. Most importantly, inhibition of RT activity in vivo antagonized tumor growth in animal experiments. Moreover, pretreatment with RT inhibitors attenuated the tumorigenic phenotype of prostate carcinoma cells inoculated in nude mice. Based on these data, the endogenous RT can be regarded as an epigenetic regulator of cell differentiation and proliferation and may represent a novel target in cancer therapy.