The natural alkaloid nitidine chloride targets RNA polymerase I to inhibit ribosome biogenesis and repress cancer cell growth
Igor K. Voukeng, Jing Chen, Denis L. J. Lafontaine
Abstract
Nature is an abundant and largely untapped source of potent bioactive molecules. Ribosome biogenesis modulators have proven effective in suppressing cancer cell growth and are currently being evaluated in clinical trials for anticancer therapies. In this study, we characterized the alkaloid nitidine chloride (NC), produced by the endemic Cameroonian plant Fagara (and other plants). We demonstrate that NC kills cancer cells regardless of their p53 status and inhibits tumor growth in vitro. Furthermore, NC profoundly suppresses global protein synthesis. Treatment of human cells with NC causes severe nucleolar disruption and inhibits pre-rRNA synthesis by destabilizing key factors required for recruitment of RNA polymerase I to ribosomal DNA promoters. In vitro, NC intercalates into DNA and inhibits topoisomerases I and II. Consistently, NC treatment activates a DNA damage response. We propose that the torsional stress on rDNA caused by topoisomerase inhibition leads to loss of RNA polymerase I function and to shutdown of ribosome biogenesis. Although NC has long been suspected of possessing anticancer properties, here we provide a molecular explanation for its mechanism of action. In budding yeast cells, interestingly, NC inhibits cell growth, impairs ribosome biogenesis, and disrupts nucleolar structure. This suggests that its mode of action is at least partially evolutionarily conserved.