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

Imke M. Willers , Antonio Isidoro , Álvaro D. Ortega , Pedro L. Fernández , José M. Cuezva (1)

1 CBMSO - Centro de Biología Molecular Severo Ochoa [Madrid]

Down-regulation of the catalytic subunit of the mitochondrial H+-ATP synthase (β-F1-ATPase) is a hallmark of many human tumors. The expression level of β-F1-ATPase provides a marker of the prognosis of cancer patients as well as of the tumor response to chemotherapy. However, the mechanisms that participate in down-regulating its expression in human tumors remain unknown. Herein, we have studied the expression of β-F1-ATPase mRNA (β-mRNA) in breast, colon and lung adenocarcinomas and squamous carcinomas of the lung. Despite the down-regulation of the protein, tumor β-mRNA levels remained either unchanged (breast and lung adenocarcinomas) or significantly increased (colon and squamous lung carcinomas) when compared to 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 of human β-mRNA is a relevant cis-acting element required for efficient translation of the transcript. However, an RNA chimera bearing the 3'UTR of human β-mRNA does not recapitulate the inhibitory effect of tumor extracts on β-mRNA translation. Overall, our findings support that the down-regulation of the bioenergetic activity of mitochondria in human tumors is exerted by translation silencing of β-mRNA.

Mots clés: Life Sciences

Imke M. Willers, Antonio Isidoro, Álvaro D. Ortega, Pedro L. Fernández, José M. Cuezva. Selective inhibition of β-F1-ATPase mRNA translation in human tumors. Biochemical Journal, 2010, 426 (3), pp.319-326. ⟨10.1042/BJ20091570⟩. ⟨hal-00479269⟩