Selective inhibition of β-F1-ATPase mRNA translation in human tumours

Abstract

Down-regulation of β-F1-ATPase (the catalytic subunit of the mitochondrial H+-ATP synthase) is a hallmark of many human tumours. The expression level of β-F1-ATPase provides a marker of the prognosis of cancer patients, as well as of the tumour response to chemotherapy. However, the mechanisms that participate in down-regulating its expression in human tumours remain unknown. In the present study, we have investigated the expression of β-F1-ATPase mRNA (termed β-mRNA) in breast, colon and lung adenocarcinomas and squamous carcinomas of the lung. Despite the down-regulation of the protein, tumour β-mRNA levels remained either unchanged (breast and lung adenocarcinomas) or significantly increased (colon and squamous lung carcinomas) when compared with paired normal tissues, suggesting a specific translation-masking event for β-mRNA in human cancer. Consistently, we show using cell-free translation assays that a large fraction (~70%) of protein extracts derived from breast and lung adenocarcinomas specifically repress the translation of β-mRNA. We show that the 3′UTR (3′ untranslated region) of human β-mRNA is a relevant cis-acting element required for efficient translation of the transcript. However, an RNA chimaera bearing the 3′UTR of human β-mRNA does not recapitulate the inhibitory effect of tumour extracts on β-mRNA translation. Overall, the findings of the present study support the hypothesis that down-regulation of the bioenergetic activity of mitochondria in human tumours is exerted by translation silencing of β-mRNA.