&lt;p&gt;5-HT&lt;sub&gt;7&lt;/sub&gt; Receptor Contributes to Proliferation, Migration and Invasion in NSCLC Cells&lt;/p&gt;

Du, Xiaohui; Wang, Ting; Wang, Zhihua; Wu, Xiaomei; Gu, Yiya; Huang, Qian; Wang, Jianmiao; Xie, Jungang

doi:10.2147/ott.s244339

Cited by 20 publications

(12 citation statements)

References 45 publications

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“…Previous studies on pancreatic cancer cell lines and human tumor tissue microarray have shown the role of 5-HT 1B , 5-HT 1D , or 5-HT 2B in 5-HT-induced cancer cell proliferation and metabolism [ 31 , 39 , 42 ]. However, the most recently discovered 5-HT receptor, 5-HT 7 , is increasingly reported as a new therapeutic target to inhibit cancer proliferation, migration, and invasion [ 28 , 42 , 43 , 44 ]. The current study demonstrated an additional important role of 5-HT 7 in inducing drug resistance and CSCs in pancreatic cancer by elucidating the mechanism regulating 5-HT 7 expression: that is, inhibition of 5-HT 7 by its antagonist or removal of 5-HT via TPH1 inhibition suppressed 5-HT 7 expression in PANC-1 and MIA PaCa-2 cells.…”

Section: Discussionmentioning

confidence: 99%

TPH1 and 5-HT7 Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma

Chaudhary

Guragain

Chang

et al. 2021

Cancers

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In the present study, we investigated the regulatory mechanisms underlying overexpression of EZH2, tryptophan hydroxylase 1 (TPH1), and 5-HT7, in relation to gemcitabine resistance and CSC survival in PDAC cells. In aggressive PANC-1 and MIA PaCa-2 cells, knock-down (KD) of EZH2, TPH1, or HTR7 induced a decrease in CSCs and recovery from gemcitabine resistance, while preconditioning of less aggressive Capan-1 cells with 5-HT induced gemcitabine resistance with increased expression of EZH2, TPH1, and 5-HT7. Such effects of the gene KD and 5-HT treatment were mediated through PI3K/Akt and JAK2/STAT3 signaling pathways. EZH2 KD or GSK-126 (an EZH2 inhibitor) inhibited activities of these signaling pathways which altered nuclear level of NF-kB, Sp1, and p-STAT3, accompanied by downregulation of TPH1 and 5-HT7. Co-immunoprecipation with EZH2 and pan-methyl lysine antibodies revealed that auto-methylated EZH2 served as a scaffold for binding with methylated NF-kB and Sp1 as well as unmethylated p-STAT3. Furthermore, the inhibitor of EZH2, TPH1, or 5-HT7 effectively regressed pancreatic tumor growth in a xenografted mouse tumor model. Overall, the results revealed that long-term exposure to 5-HT upregulated EZH2, and the noncanonical action of EZH2 allowed the expression of TPH1-5-HT7 axis leading to gemcitabine resistance and CSC population in PDAC.

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Section: Discussionmentioning

confidence: 99%

TPH1 and 5-HT7 Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma

Chaudhary

Guragain

Chang

et al. 2021

Cancers

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“…Of the dozen or so 5-HT receptors currently recognized, 5-HT receptor 7 (5-HT7) is expressed on GB cells where agonism enhances growth [50][51][52]. This same finding of growth drive stimulation via 5-HT7 is also found in non-small cell lung adenocarcinoma where 5-HT7 agonism drives proliferation, migration, and invasion [53]. Similar growth stimulation by 5-HT7 was seen in neuroendocrine tumors [54], hepatocellular carcinoma [55], and triple negative breast cancer [56,57] 7.…”

Section: 5mentioning

confidence: 85%

2. Adding perphenazine to increase effectiveness of standard glioblastoma chemoirradiation.

Kast¹

2020

Preprint

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In the effort to improve treatment effectiveness in glioblastoma, this short note reviewed collected data on the pathophysiology of glioblastoma with particular reference to intersections with the pharmacology of perphenazine. That study identified five areas of potentially beneficial intersection. Data showed seemingly 5 independent perphenazine attributes of benefit to glioblastoma treatment -i) blocking dopamine receptor 2, ii) reducing centrifugal migration of subventricular zone cells by blocking dopamine receptor 3, iii) blocking serotonin receptor 7, iv) activation of protein phosphatase 2, and v) nausea reduction. Perphenazine is fully compatible with current chemoirradiation protocols and with the commonly used ancillary medicines used in clinical practice during the course of glioblastoma. All these attributes argue for a trial of perphenazine's addition to current standard treatment with temozolomide and irradiation. The subventricular zone seeds the brain with mutated cells that become recurrent glioblastoma after centrifugal migration. The current paper shows how perphenazine might reduce that contribution. Perphenazine is an old, generic, cheap, phenothiazine antipsychotic drug that has been in continuous clinical use worldwide since the 1950's. Clinical experience and research data over these decades have shown perphenazine to be well-tolerated in psychiatric populations, in normals, and in non-psychiatric, medically ill populations for whom perphenazine is used to reduce nausea. For now (Summer, 2020) the nature of glioblastoma requires a polypharmacy approach until/unless a core feature and means to address it can be identified in the future. Conclusions: Perphenazine possesses a remarkable constellation of attributes that recommend its use in GB treatment.2. Adding perphenazine to increase effectiveness of standard glioblastoma chemoirradiation.

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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%

“…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 ]. Similarly, KD of 5-HTR1B dampens the proliferation, migration, and invasive properties of non-small cell lung carcinoma [ 67 ]. In acute myeloid leukemia (AML), 5-HTR1B has a functional role in maintaining therapy-resistant leukemic stem cells [ 66 ].…”

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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<p>5-HT<sub>7</sub> Receptor Contributes to Proliferation, Migration and Invasion in NSCLC Cells</p>

Cited by 20 publications

References 45 publications

TPH1 and 5-HT7 Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma

TPH1 and 5-HT7 Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma

2. Adding perphenazine to increase effectiveness of standard glioblastoma chemoirradiation.

The Role of Serotonin in Breast Cancer Stem Cells

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