5-hydroxytryptamine synthesized in the aorta-gonad-mesonephros regulates hematopoietic stem and progenitor cell survival

Lv, Juan; Wang, Lu; Liu, Feng

doi:10.1016/j.mod.2017.04.485

Cited by 7 publications

(9 citation statements)

References 22 publications

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“…These data suggest that MAMPs are constituently present in the circulation of conventionally housed mice and provide tonic signals to the hematopoietic compartment. In contrast, reports have identified microbial-derived metabolites that also regulate hematopoiesis, including short-chain fatty acids (42), bile acids (43), and amino acids (44). Future research will need to confirm whether one or more of these microbial-derived molecules is capable of priming microbiota-dependent inflammation-induced myelopoiesis to yield insight into the molecular mechanisms governing how host-commensal interactions tune systemic TLR-driven innate immune responses by regulating the production of new hematopoietically derived myeloid cells.…”

Section: Discussionmentioning

confidence: 96%

Microbiota-dependent signals are required to sustain TLR-mediated immune responses

Weaver¹,

Minichino²,

Biswas³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 96%

Microbiota-dependent signals are required to sustain TLR-mediated immune responses

Weaver¹,

Minichino²,

Biswas³

et al. 2019

JCI Insight

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“…A recent study showed that inhibition of PI3K or AKT1 reduces the frequency of BTIC-enriched CD44 High /CD24 Low breast tumor cells by initiating their apoptosis via FOXO3a and Bim [45]. Moreover, inhibition of 5-HT5A with SB-699551 affects the survival of mouse embryonic hematopoietic progenitor cells by reducing the phosphorylation of AKT and FOXO1, and increasing the abundance of FOXO1 and Bim [35]. Hence our hypothesis that SB-699551 targets BTIC in part by inhibiting AKT/FOXO signaling is consistent with the reports of others.…”

Section: Discussionmentioning

confidence: 99%

“…AKT mediates cell survival by phosphorylating the forkhead box protein 1 (FOXO1) transcription factor [35]. Phosphorylated FOXO1 (pFOXO1) is sequestered in the cytosol preventing it from effecting the transcription of pro-apoptotic genes such as BIM, a member of the BCL2 gene family.…”

Section: Treatment Of Breast Tumor Cell Lines With Sb-699551 Affects mentioning

confidence: 99%

Antagonists of the serotonin receptor 5A target human breast tumor initiating cells

et al. 2020

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Background: Breast tumor initiating cells (BTIC) are stem-like cells that initiate and sustain tumor growth, and drive disease recurrence. Identifying therapies targeting BTIC has been hindered due primarily to their scarcity in tumors. We previously reported that BTIC frequency ranges between 15% and 50% in multiple mammary tumors of 3 different transgenic mouse models of breast cancer and that this frequency is maintained in tumor cell populations cultured in serum-free, chemically defined media as non-adherent tumorspheres. The latter enabled high-throughput screening of small molecules for their capacity to affect BTIC survival. Antagonists of several serotonin receptors (5-HTRs) were among the hit compounds. The most potent compound we identified, SB-699551, selectively binds to 5-HT5A, a Gα i/o protein coupled receptor (GPCR). Methods: We evaluated the activity of structurally unrelated selective 5-HT5A antagonists using multiple orthogonal assays of BTIC frequency. Thereafter we used a phosphoproteomic approach to uncover the mechanism of action of SB-699551. To validate the molecular target of the antagonists, we used the CRISPR-Cas9 gene editing technology to conditionally knockout HTR5A in a breast tumor cell line. Results: We found that selective antagonists of 5-HT5A reduced the frequency of tumorsphere initiating cells residing in breast tumor cell lines and those of patient-derived xenografts (PDXs) that we established. The most potent compound among those tested, SB-699551, reduced the frequency of BTIC in ex vivo assays and acted in concert with chemotherapy to shrink human breast tumor xenografts in vivo. Our phosphoproteomic experiments established that exposure of breast tumor cells to SB-699551 elicited signaling changes in the canonical Gα i/o-coupled pathway and the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) axis. Moreover, conditional mutation of the HTR5A gene resulted in the loss of tumorsphere initiating cells and BTIC thus mimicking the effect of SB-699551. Conclusions: Our data provide genetic, pharmacological and phosphoproteomic evidence consistent with the ontarget activity of SB-699551. The use of such agents in combination with cytotoxic chemotherapy provides a novel therapeutic approach to treat breast cancer.

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“…Mice deficient in peripheral 5-HT synthetizing enzyme, Tph1 -/mice, displayed morphological and cellular features of ineffective erythropoiesis; in the bone marrow, the absence of 5-HT limited the differentiation of erythroid precursors expressing 5-HT 2A and 5-HT 2B receptors [25]. In Tph2 -/--deficient embryos, a decrease in 5-HT synthesized in the aorta-gonad-mesonephros leads to apoptosis of nascent hematopoietic stem cells; 5-HT inhibits the Akt-Foxo1 signaling cascade and protects hematopoietic stem cells from excessive apoptosis [26]. Furthermore, 5-HT significantly enhanced the amount of early stem/progenitors and multilineage committed progenitors (burstforming unit/colony-forming unit-erythroid, colony-forming unit-granulocyte macrophage, and colony-forming unit-megakaryocyte lineages) [27] during adult hematopoiesis.…”

Section: -Ht and Hematopoiesismentioning

confidence: 99%

Frontiers of Serotonin Beyond the Brain

Maroteaux

Kilic

2019

Pharmacological Research

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Long time before its identification as 5-hydroxytryptamine (5-HT), the first described effect of serotonin was a cardiovascular action. At the end of 19th century, a substance present in serum, (thrombosed blood fraction), was found to act on heart and blood vessels: in 1896, Weiss showed that intravenous injection of serum into an animal caused an increase in breathing and cardiac frequencies, followed by a rapid decrease in blood pressure leading eventually to death [1]. In 1918, it was reported that citrated serum or blood platelet extract was vasoconstrictor, while uncoagulated blood or citrated plasma did not have a vasoconstrictor action [2]. In 1930, a substance, called enteramine, which contracted smooth muscles was isolated from intestinal enterochromaffin cells [3]. Finally, in late 1940s, a vasoconstrictor substance called serotonin was identified as 5-hydroxytryptamine [4, 5].

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5-hydroxytryptamine synthesized in the aorta-gonad-mesonephros regulates hematopoietic stem and progenitor cell survival

Cited by 7 publications

References 22 publications

Microbiota-dependent signals are required to sustain TLR-mediated immune responses

Microbiota-dependent signals are required to sustain TLR-mediated immune responses

Antagonists of the serotonin receptor 5A target human breast tumor initiating cells

Frontiers of Serotonin Beyond the Brain

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