ABSTRACT
The licensed drug rapamycin has potential to be repurposed for geroprotection. A key challenge is to avoid adverse side effects from continuous dosing. Here we show that geroprotective effects of chronic rapamycin treatment can be obtained with a brief pulse of the drug in early adulthood in female Drosophila and mice. In Drosophila, a brief, early rapamycin treatment of adults extended lifespan and attenuated age-related decline in the intestine to the same degree as lifelong dosing. Lasting memory of earlier treatment was mediated by elevated autophagy in intestinal enterocytes, accompanied by increased levels of intestinal LManV and lysozyme. Brief elevation of autophagy in early adulthood itself induced a long-term increase in autophagy. In mice, a 3-month, early treatment also induced a memory effect, with maintenance similar to chronic treatment, of lysozyme distribution, Man2B1 level in intestinal crypts, Paneth cell architecture and gut barrier function, even 6 months after rapamycin was withdrawn.
Subject(s)
Muramidase , Sirolimus , Animals , Female , Mice , Sirolimus/pharmacology , Muramidase/pharmacology , Paneth Cells , Drosophila , AutophagyABSTRACT
In adult epithelial stem cell lineages, the precise differentiation of daughter cells is critical to maintain tissue homeostasis. Notch signaling controls the choice between absorptive and entero-endocrine cell differentiation in both the mammalian small intestine and the Drosophila midgut, yet how Notch promotes lineage restriction remains unclear. Here, we describe a role for the transcription factor Klumpfuss (Klu) in restricting the fate of enteroblasts (EBs) in the Drosophila intestine. Klu is induced in Notch-positive EBs and its activity restricts cell fate towards the enterocyte (EC) lineage. Transcriptomics and DamID profiling show that Klu suppresses enteroendocrine (EE) fate by repressing the action of the proneural gene Scute, which is essential for EE differentiation. Loss of Klu results in differentiation of EBs into EE cells. Our findings provide mechanistic insight into how lineage commitment in progenitor cell differentiation can be ensured downstream of initial specification cues.
Subject(s)
Cell Lineage , DNA-Binding Proteins/metabolism , Drosophila Proteins/metabolism , Drosophila melanogaster/cytology , Enterocytes/cytology , Intestines/cytology , Stem Cells/cytology , Transcription Factors/metabolism , Animals , Carcinogenesis/metabolism , Carcinogenesis/pathology , Cell Differentiation , Cell Proliferation , Models, Biological , Protein Binding , Receptors, Notch/metabolism , Signal Transduction , Stem Cells/metabolismABSTRACT
BACKGROUND: Colorectal cancer (CRC) is known as one of the most leading causes of death from cancer in the world. Wnt signaling pathway is the most important signaling pathway activated in this type of cancer. The low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) functions as a co-receptor in order to trigger this signaling pathway. OBJECTIVE: The expression of LRP6 was studied in cell lines, tumoral and normal adjacent tissues from patients affected with colorectal cancer. MATERIALS AND METHODS: The expression of LRP6 was assayed by quantitative Real time PCR. RESULTS: LRP6 is overexpressed at the transcript and protein level in HCT116 and SW480 in comparison to HUVEC as the non-cancerous cell. Furthermore, LRP6 was significantly up-regulated in 61% of human malignant tissues (p-value = 0.0008). In inherited type of disease, this upregulation was lower than other types of colorectal cancer, while in rectal cancer the overexpression was significantly higher (p-value = 0.039). Gene expression was not correlated with the age, gender and the stage of disease. CONCLUSION: Due to the profound overexpression of LRP6 in sporadic and rectal types of cancer compared to normal colonic ones, antagonist related approaches can be promising for targeted therapies of cancer.
