Interference with energy metabolism by 5-aminoimidazole-4-carboxamide-1-{beta}-D-ribofuranoside induces HPV suppression in cervical carcinoma cells and apoptosis in the absence of LKB1

Julia Nafz , Johanna De-Castro Arce , Verena Fleig , Andrea Patzelt , Sybille Mazurek , Frank Rösl , Frank Rösl (1)

1 Viral Transformation Mechanisms

Carcinogenesis is a dynamic and stepwise process, which is accompanied by a variety of somatic and epigenetic alterations in response to a changing microenvironment. Hypoxic conditions will select for cells, which have adjusted their metabolic profile and maintain proliferation by successfully competing for scarce nutritional and oxygen resources. In the present report we have studied the effects of energy depletion in the context of HPV-induced pathogenesis. We show that cervical carcinoma cell lines are susceptible to undergo either growth arrest or cell death under conditions of metabolic stress induced by 5-aminoimidazole-4-carboxamide-1-{beta}-D-ribofuranoside (AICAR), a known activator of the AMP-activated protein kinase (AMPK). Our results revealed that AICAR treatment led to a reduced binding affinity of the transcription factor AP-1 and in turn to a selective suppression of HPV transcription. Moreover, the outcome of AICAR on proliferation and survival was dependent on p53 activation and the presence of LKB1, the major upstream kinases of AMPK. Using non-malignant LKB1 expressing somatic cell hybrids, which lose expression after tumourigenic segregation as well as siRNA LKB1 knock-down approaches, we could further demonstrate that expression of LKB1 protects cells from cytotoxicity induced by agents which modulate the ATP:AMP ratio. Since simulation of low energy status can selectively eradicate LKB1 negative cervical carcinoma cells, AICAR may represent a novel drug in the treatment of cervical cancer.

Mots clés: Life Sciences

Julia Nafz, Johanna De-Castro Arce, Verena Fleig, Andrea Patzelt, Sybille Mazurek, et al.. Interference with energy metabolism by 5-aminoimidazole-4-carboxamide-1-{beta}-D-ribofuranoside induces HPV suppression in cervical carcinoma cells and apoptosis in the absence of LKB1. Biochemical Journal, 2007, 403 (3), pp.501-510. ⟨10.1042/BJ20061053⟩. ⟨hal-00478629⟩