{"id":2675,"date":"2024-08-26T13:54:17","date_gmt":"2024-08-26T17:54:17","guid":{"rendered":"http:\/\/haidut.me\/?p=2675"},"modified":"2024-08-26T13:54:17","modified_gmt":"2024-08-26T17:54:17","slug":"serotonin-promotes-own-synthesis-activates-warburg-effect-drives-breast-colon-pancreatic-cancer","status":"publish","type":"post","link":"https:\/\/haidut.me\/?p=2675","title":{"rendered":"Serotonin promotes own synthesis, activates Warburg Effect, drives breast\/colon\/pancreatic cancer"},"content":{"rendered":"

Just a few days ago I posted about a study showing that serotonin (5-HT) plays a role in driving the growth of a rare but lethal pediatric cancer. The authors of that study opined that the growth-promoting effects of 5-HT are generic enough that they may apply to all cancers. The studies below corroborate that view with evidence that 5-HT forms a positive feedback cycle for its production<\/strong><\/span> (just like cortisol, which also drives cancer growth) by increasing both the expression and activity of the enzyme tryptophan hydroxylase (TPH) – i.e. the 5-HT producing enzyme. Apparently, 5-HT also activates aerobic glycolysis, known as the Warburg Effect (WE). The WE was considered up until very recently a benign symptom of cancer, but not oncogenic. Recent studies have completely disproved that view and it is now known that the WE is a required factor for growth of ALL cancer types studied so far. In light of these effects, it is little wonder that the studies below found 5-HT to be a robust promoter of the growth of breast, colon and pancreatic cancers, the first two of which combined are responsible for the majority of cancer cases and cancer-related deaths. In further corroboration, one of the studies identified 5-HT as a diagnostic biomarker in breast cancer that not only reliably predicts whether a specific tissue\/organ is cancerous, but also predicts the severity\/aggressiveness of the tumor. Namely, serotonin levels were found to be highest in the most aggressive and difficult to treat triple-negative breast cancer. Conversely, the studies describe therapeutic effects of 5-HT antagonists in the studied cancers, which has already been corroborated by a recent peer-reviewed human case study demonstrating complete disappearance of terminal, metastatic liver cancer by monotherapy with the non-selective 5-HT antagonist cyproheptadine.<\/p>\n

The evidence for the oncogenic role of 5-HT is, in fact, so strong that one of the studies stated that 5-HT is required for (breast) cancer survival<\/strong><\/span>, meaning without 5-HT the tumor disappears or, better, does not even form in the first place. So, now we can add cancer to the CVD that 5-HT is also implicated in causing, and those two maladies just happen to be the top two causes of death in all developed countries. In light of this evidence, one would be forgiven to conclude that SSRI drugs (widely prescribed to cancer patients to “prevent” or “treat” their depression\/PTSD from the cancer diagnosis) are likely a major causative factor for the skyrocketing rates of those conditions, as well as the deaths they cause. In corroboration, one of the studies below mentions extensive evidence for SSRI both promoting cancer formation, as well as increasing the mortality rates of already diagnosed cancer patients.<\/p>\n

https:\/\/www.nature.com\/articles\/s41388-022-02584-4<\/a><\/p>\n

“…Serotonin (5-hydroxytryptamine, 5-HT) is synthesized from the essential amino acid tryptophan and mediates motility in the gastrointestinal tract and is a vasoactive agent in the blood. As a monoamine neurotransmitter, it also acts in the central nervous system. It regulates epithelial homeostasis in the breast. Serotonin is believed to impact immune signaling and stimulate growth of breast cancer cells [57<\/a>,58<\/a>,59<\/a>,60<\/a>,61<\/a>]. Olfati et al. showed that in samples from breast cancer patients, 5HTR2A and 5HTR3A genes are more expressed in tumoral tissues than marginal tissues [62<\/a>]. Serotonin also initiates angiogenesis<\/strong><\/span> by the proliferation, invasion, and migration of endothelial cells [63<\/a>]. Sonier et al. found that serotonin promotes the growth and division of breast cancer<\/strong><\/span> cells, specifically MCF-7 cells, in part through the 5-HT2A<\/sub>\u00a0receptor. Proliferation and invasion is also facilitated by the 5-HT7<\/sub>\u00a0receptor in MDA-MB-231 cells. In these cells, 5-HT is essential to enhance the expression of TPH1<\/strong><\/span> (tryptophan hydroxylase 1) and VEGF, supporting the mitogenic and oncogenic impact of 5-HT<\/strong><\/span> on breast cancer.”<\/p>\n

“…If lowering serotonin activity reduces breast cancer recurrence, then a logical question is the impact of medications that raise serotonin levels. Evidence has been conflicting on this long-standing question. Two decades ago, researchers reported that use of tricyclic medications was associated with significantly increased breast cancer risk [66<\/a>,\u00a067<\/a>] and that use of selective serotonin reuptake inhibitor (SSRI) drugs may also pose a breast cancer risk<\/strong><\/span> [68<\/a>,\u00a069<\/a>]. The SSRI fluoxetine may increase the number of breast cancer brain metastases<\/span> at least in part due to inflammatory changes in the brain<\/strong><\/span> [70<\/a>]. Supporting these contentions, this year researchers in Israel reported based on an analysis of 7000 patients that use of SSRIs<\/strong><\/span> in the years prior to breast cancer diagnosis, or in the years following diagnosis, was associated with substantially increased mortality<\/strong><\/span> [71<\/a>].”<\/p>\n

https:\/\/pubmed.ncbi.nlm.nih.gov\/32758183\/<\/a><\/p>\n

“…The data presented herein strongly suggests that structurally unrelated selective 5-HT5A antagonists reduce the frequency of tumorsphere initiating cells<\/strong><\/span> by affecting the activity of 5-HT5A. The latter is supported by our pharmacological data demonstrating that the IC50<\/sub>\u00a0of the guanidine-type 5-HT5A antagonists in sphere forming assays directly correlated with their binding affinity for 5-HT5A [24<\/a>,\u00a036<\/a>]. Moreover, CRISPR-Cas9 mediated mutagenesis of\u00a0HTR5A<\/em> reduced the frequency of tumorsphere initiating cells and that of BTIC using in vitro and ex vivo assays, thus mimicking the effect of SB-699551. Hence both pharmacological<\/strong><\/span> and genetic means of reducing 5-HT5A activity resulted in the same phenotypic consequences in breast tumor cell lines, suggesting<\/strong> that<\/strong> <\/span>5-HT5A is indeed required for BITC survival<\/strong><\/span>. We also found that SB-699551 reduces the growth rate of human breast tumor<\/strong><\/span> xenografts in NOD\/SCID mice when administered alone and shrinks the xenografts<\/strong><\/span> in combination with docetaxel. Histological examination and TUNEL assays revealed an increase in the frequency of apoptotic tumor cells<\/strong><\/span> in the xenografts of mice treated with a combination of both agents<\/strong><\/span>.\u00a0”<\/p>\n

https:\/\/doi.org\/10.1158\/1541-7786.MCR-23-0513<\/a><\/p>\n

“…A number of neurotransmitters have been detected in tumor microenvironment and proved to modulate cancer oncogenesis and progression. We previously found that biosynthesis and secretion of neurotransmitter 5-hydroxytryptamine (5-HT) was elevated in colorectal cancer cells<\/strong><\/span>. In this study, we discovered that the HTR2B receptor of 5-HT was highly expressed in colorectal cancer<\/strong><\/span> tumor tissues, which was further identified as a strong risk factor for colorectal cancer prognostic outcomes<\/strong><\/span>. Both pharmacological blocking and genetic knocking down HTR2B impaired migration of colorectal cancer cell<\/strong><\/span>, as well as the epithelial\u2013mesenchymal transition (EMT) process. Mechanistically, HTR2B signaling induced ribosomal protein S6 kinase B1 (S6K1) activation via the Akt\/mTOR pathway, which triggered cAMP-responsive element-binding protein 1 (CREB1) phosphorylation (Ser 133) and translocation into the nucleus, then the phosphorylated CREB1 acts as an activator for\u00a0ZEB1<\/em>\u00a0transcription after binding to CREB1 half-site (GTCA) at\u00a0ZEB1<\/em>\u00a0promoter. As a key regulator of EMT, ZEB1, therefore, enhances migration and EMT process in colorectal cancer cells. We also found that HTR2B-specific antagonist (RS127445) treatment significantly ameliorated metastasis and reversed EMT process<\/strong><\/span> in both HCT116 cell tail-vein\u2013injected pulmonary metastasis and CT26 cell intrasplenic-injected hepatic metastasis mouse models.”<\/p>\n

https:\/\/doi.org\/10.2147\/IJGM.S310591<\/p>\n

“…Our results suggested that both human breast cancer cells and human breast epithelial cell line could synthesize serotonin and melatonin<\/strong><\/span>. Unlike melatonin, serotonin levels varied significantly between human breast cancer and breast epithelial cell line (p<\/em>< 0.01). In addition, serotonin N-acetyltransferase (NAT) and acetylserotonin methyltransferase (ASMT), the key enzymes in the pathway of melatonin synthesis from serotonin, were also detectable. In agreement with these findings of human breast cancer cell and human breast epithelial cell line, serotonin expression was also much higher in triple-negative (PR\u2212, ER\u2212, HER-2\u2212<\/sup>) breast cancer (TNBC) and triple-positive breast cancer (TPBC) compared to para-carcinoma tissues (PCTs)<\/strong><\/span>. Here, we provided evidence that the human breast cancer cell (MCF-7, Bcap-37) and human breast epithelial cell (MCF-10A) could synthesize intrinsic serotonin and melatonin, and serotonin expression was higher in the breast cancer tissue compared with PCT. The findings suggested that serotonin might be used as a predictive marker for breast cancer patients<\/strong><\/span>.”<\/p>\n

https:\/\/doi.org\/10.1053\/j.gastro.2017.03.008<\/a><\/p>\n

“…In immunohistochemical analysis of a tissue microarray of PDAC specimens, increased levels of TPH1 and decreased level of MAOA<\/strong><\/span>, which regulate 5-HT synthesis and degradation, correlated with stage and size of PDACs and shorter patient survival time<\/strong><\/span>. We found levels of 5-HT to be increased in human PDAC tissues compared with non-tumor pancreatic tissues<\/strong><\/span>, and PDAC cell lines compared with non-transformed pancreatic cells. Incubation of PDAC cell lines with 5-HT increased proliferation and prevented apoptosis<\/strong><\/span>. Agonists of HTR2B<\/strong><\/span>, but not other 5-HT receptors, promoted proliferation and prevented apoptosis of PDAC cells<\/strong><\/span>. Knockdown of HTR2B in PDAC cells, or incubation of cells with HTR2B inhibitors, reduced their growth<\/strong><\/span> as xenograft tumors in mice. We observed a correlation between 5-HT and glycolytic flux<\/strong><\/span> in PDAC cells; levels of metabolic enzymes involved in glycolysis, the phosphate pentose pathway, and hexosamine biosynthesis pathway increased significantly in PDAC cells following 5-HT stimulation. 5-HT stimulation led to<\/strong><\/span> formation of the HTR2B\u2013LYN\u2013p85 complex, which increased PI3K\u2013Akt\u2013mTOR signaling and the Warburg effect<\/strong><\/span> by increasing protein levels of MYC and HIF1A. Administration of SB204741<\/strong><\/span> to KPC mice slowed growth and metabolism of established pancreatic tumors and prolonged survival<\/strong><\/span> of the mice. Human PDACs have increased levels of 5-HT<\/strong><\/span>, and PDAC cells increase expression of its receptor, HTR2B. These increases allow for tumor glycolysis under metabolic stress and promote growth of pancreatic tumors<\/strong><\/span> and PDAC xenograft tumors in mice.”<\/p>\n","protected":false},"excerpt":{"rendered":"

Just a few days ago I posted about a study showing that serotonin (5-HT) plays a role…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[2],"tags":[192,2054,55,56,373,2055,1499,47,374],"class_list":["post-2675","post","type-post","status-publish","format-standard","hentry","category-science","tag-5-ht","tag-breast","tag-cancer","tag-colon","tag-glycolysis","tag-oncogenic","tag-pancreatic","tag-serotonin","tag-warburg","wpcat-2-id"],"_links":{"self":[{"href":"https:\/\/haidut.me\/index.php?rest_route=\/wp\/v2\/posts\/2675","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/haidut.me\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/haidut.me\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/haidut.me\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/haidut.me\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=2675"}],"version-history":[{"count":1,"href":"https:\/\/haidut.me\/index.php?rest_route=\/wp\/v2\/posts\/2675\/revisions"}],"predecessor-version":[{"id":2676,"href":"https:\/\/haidut.me\/index.php?rest_route=\/wp\/v2\/posts\/2675\/revisions\/2676"}],"wp:attachment":[{"href":"https:\/\/haidut.me\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=2675"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/haidut.me\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=2675"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/haidut.me\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=2675"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}