PT  - JOURNAL ARTICLE
AU  - Roxana M. Pfefferkorn
AU  - Benedikt M. Mortzfeld
AU  - Christine Fink
AU  - Jakob von Frieling
AU  - Judith Bossen
AU  - Daniela Esser
AU  - Christoph Kaleta
AU  - Philip Rosenstiel
AU  - Holger Heine
AU  - Thomas Roeder
TI  - Recurrent phases of strict protein limitation inhibit tumor growth and restore lifespan in a <em>Drosophila</em> intestinal cancer model
AID  - 10.1101/2023.01.18.524563
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.01.18.524563
4099  - http://biorxiv.org/content/early/2023/01/20/2023.01.18.524563.short
4100  - http://biorxiv.org/content/early/2023/01/20/2023.01.18.524563.full
AB  - Diets that restrict caloric or protein intake offer a variety of benefits, including decreasing the incidence of cancer. However, whether such diets pose a substantial therapeutic benefit as auxiliary cancer treatments remains unclear. We determined the effects of severe protein depletion on tumorigenesis in a Drosophila melanogaster intestinal tumor model, using a human RAF gain-of-function allele. Severe and continuous protein restriction significantly reduced tumor growth but resulted in premature death. Therefore, we developed a diet in which short periods of severe protein restriction alternated cyclically with periods of complete feeding. This nutritional regime reduced tumor mass, restored gut functionality, and normalized the lifespan of oncogene-expressing flies to the levels observed in healthy control flies. Furthermore, this diet reduced the chemotherapy-induced stem cell activity associated with tumor recurrence. Transcriptome analysis revealed long-lasting changes in the expression of key genes involved in multiple major developmental signaling pathways. Overall, the data suggest that recurrent severe protein depletion effectively mimics the health benefits of continuous protein restriction, without undesired nutritional shortcomings. This provides seminal insights into the mechanisms of the transcriptomic memory effect required to maintain the positive effects of protein restriction throughout the phases of a full diet.Competing Interest StatementThe authors have declared no competing interest.