Serotonin receptor type 1B constitutes a therapeutic target for MDS and CMML

Banús-Mulet, Antònia; Etxabe, Amaia; Cornet-Masana, Josep M.; Torrente, Miguel; Lara-Castillo, María Carmen; Palomo, Laura; Nomdedéu, Meritxell; Díaz‐Beyá, Marina; Solé, Françesc; Nomdedeu, Benet; Esteve, Jordi; Risueño, Ruth M.

doi:10.1038/s41598-018-32306-4

Cited by 12 publications

(9 citation statements)

References 49 publications

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“…5‐Hydroxyl‐ l ‐tryptophan, composed of the essential amino acid l ‐tryptophan, is a direct precursor to the neurotransmitter serotonin. Previous studies have shown that serotonin promotes the growth and proliferation of erythroid progenitors (Banus‐Mulet et al, 2018; Sibon et al, 2019). The increased concentration of 5‐hydroxyl‐ l ‐tryptophan in MDS patients may be due to the lack of aromatic l ‐amino acid decarboxylase and the decrease of serotonin synthesis.…”

Section: Discussionmentioning

confidence: 99%

Integrative metabolic profile of myelodysplastic syndrome based on UHPLC–MS

Yuan

Zhao

et al. 2021

Biomedical Chromatography

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Myelodysplastic syndrome (MDS) is a neoplastic disease originating from hematopoietic stem cells. Currently, hematopoietic stem cell transplantation (HSCT) is the most effective cure, although lenalidomide, azacytidine, and decitabine have been applied to relieve symptoms of MDS. The purpose of this study was to evaluate the changes in endogenous metabolites by applying a UHPLC–MS (ultra–high‐performance liquid chromatography–MS) metabolomics approach and to investigate metabolic pathways related to MDS. An untargeted metabolomics approach based on UHPLC–MS in combination with multivariate data analysis, including partial least squares discrimination analysis and orthogonal partial least squares discriminant analysis, was established to investigate potential biomarkers in the plasma of MDS patients. As a result, 29 biomarkers were identified to distinguish between MDS patients, HSCT patients, and healthy controls, which were mainly related to inflammation regulation, amino acid metabolism, fatty acid metabolism, and energy metabolism. To our knowledge, this is the first time where plasma metabolomics was combined with HSCT to study the pathogenesis and therapeutic target of MDS. The identification of biomarkers and analysis of metabolic pathways could offer the possibility of discovering new therapeutic targets for MDS in the future.

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Section: Discussionmentioning

confidence: 99%

Integrative metabolic profile of myelodysplastic syndrome based on UHPLC–MS

Yuan

Zhao

et al. 2021

Biomedical Chromatography

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“…Further work is needed to identify the protective mechanisms elicited by osteoblasts and to clarify their role versus the role of peripheral serotonin signaling during disease growth. HTR1B has been previously proposed to promote AML growth (51,52) through its expression on AML cells, mainly based on the observation that pharmacological inhibition of HTR1B improves disease outcome in vivo. This work however did not differentiate or directly assess the possibility that HTR1B signaling in BM stromal -not AML-cells may contribute to these actions.…”

Section: Discussionmentioning

confidence: 99%

Subversion of Serotonin Receptor Signaling in Osteoblasts by Kynurenine Drives Acute Myeloid Leukemia

et al. 2022

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Remodeling of the microenvironment by tumor cells can activate pathways that favor cancer growth. Molecular delineation and targeting of such malignant-cell nonautonomous pathways may help overcome resistance to targeted-therapies. Herein we leverage genetic mouse models, patient-derived xenografts, and patient samples to show that acute myeloid leukemia (AML) exploits peripheral serotonin-signaling to remodel the endosteal niche to its advantage. AML progression requires the presence of serotonin receptor-1b (HTR1B) in osteoblasts and is driven by AML-secreted kynurenine, which acts as an oncometabolite and HTR1B ligand. AML cells utilize kynurenine to induce a pro-inflammatory state in osteoblasts which, through the acutephase protein serum amyloid A (SAA), acts in a positive feedback-loop on leukemia cells by increasing expression of IDO1 -the rate-limiting enzyme for kynurenine synthesis-, thereby enabling AML progression. This leukemia-osteoblast crosstalk, conferred by the kynurenine-HTR1B-SAA-IDO1 axis, could be exploited as a nichefocused therapeutic approach against AML, opening new avenues for cancer treatment. SIGNIFICANCE AML remains recalcitrant to treatments due to the emergence of resistant clones. We show a leukemia-cell non-autonomous progression mechanism that involves activation of a kynurenine-HTR1B-SAA-IDO1 axis between AML cells and osteoblasts. Targeting the niche by interrupting this axis can be pharmacologically harnessed to hamper AML progression and overcome therapy resistance.

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“…A functional role for 5-HTRs in human cancers and cancer stem cells is not exclusive to breast cancer, and the genetic depletion of 5-HTRs has deleterious consequences in several tumors of other solid organs and hematological malignancies [ 65 , 66 , 67 , 68 ]. For example, KD of 5-HTR1B and 5-HTR1D inhibits the proliferation and clonogenic capacity of pancreatic tumor cells by inhibiting the activity of transcription factors involved in initiating an EMT [ 68 ].…”

Section: 5-ht and Human Cancersmentioning

confidence: 99%

“…In acute myeloid leukemia (AML), 5-HTR1B has a functional role in maintaining therapy-resistant leukemic stem cells [ 66 ]. Hence, 5-HTR1B has been proposed as a therapeutic target for AML, myelodysplastic syndromes, and chronic myelomonocytic leukemia [ 65 ]. Of note, one of the tool compounds used to inhibit 5-HTR1B in the latter studies, SB-224289, also demonstrated efficacy against BTIC ( Table 2 ) [ 22 , 43 ].…”

Section: 5-ht and Human Cancersmentioning

confidence: 99%

The Role of Serotonin in Breast Cancer Stem Cells

et al. 2021

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Breast tumors were the first tumors of epithelial origin shown to follow the cancer stem cell model. The model proposes that cancer stem cells are uniquely endowed with tumorigenic capacity and that their aberrant differentiation yields non-tumorigenic progeny, which constitute the bulk of the tumor cell population. Breast cancer stem cells resist therapies and seed metastases; thus, they account for breast cancer recurrence. Hence, targeting these cells is essential to achieve durable breast cancer remissions. We identified compounds including selective antagonists of multiple serotonergic system pathway components required for serotonin biosynthesis, transport, activity via multiple 5-HT receptors (5-HTRs), and catabolism that reduce the viability of breast cancer stem cells of both mouse and human origin using multiple orthologous assays. The molecular targets of the selective antagonists are expressed in breast tumors and breast cancer cell lines, which also produce serotonin, implying that it plays a required functional role in these cells. The selective antagonists act synergistically with chemotherapy to shrink mouse mammary tumors and human breast tumor xenografts primarily by inducing programmed tumor cell death. We hypothesize those serotonergic proteins of diverse activity function by common signaling pathways to maintain cancer stem cell viability. Here, we summarize our recent findings and the relevant literature regarding the role of serotonin in breast cancer.

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Serotonin receptor type 1B constitutes a therapeutic target for MDS and CMML

Cited by 12 publications

References 49 publications

Integrative metabolic profile of myelodysplastic syndrome based on UHPLC–MS

Integrative metabolic profile of myelodysplastic syndrome based on UHPLC–MS

Subversion of Serotonin Receptor Signaling in Osteoblasts by Kynurenine Drives Acute Myeloid Leukemia

The Role of Serotonin in Breast Cancer Stem Cells

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