Antiproliferative activity of melatonin by transcriptional inhibition of cyclin D1 expression: a molecular basis for melatonin-induced oncostatic effects
Abstract
Melatonin is endowed with a growth inhibitory effect in MCF-7 breast cancer cells whose mechanism has been related to an antiestrogenic activity exerted by inhibition of binding of the estradiol-estrogen receptor complex to its DNA responsive element. Looking for downstream gene determinants of this effect, we performed a transcriptome profiling by high-density microarrays of estrogen-treated MCF-7 cells exposed or not to melatonin.
We found that cyclin D1 was one of the main downregulated genes by melatonin. Validation experiments clearly confirm that in MCF-7 cells the estrogen-induced growth inhibitory activity of melatonin is consistently associated with inhibition of estrogen-elicited cyclin D1 induction. This effect is almost purely transcriptional. Reporter gene assays indicate that the same portion of the cyclin D1 promoter which confers estrogen sensitivity, encompassing a potential cAMP responsive element binding site, is repressed by melatonin. Transcriptional downregulation of cyclin D1 is the key molecular event for melatonin's antiproliferative activity, as this activity can be completely and selectively rescued by transient cyclin D1 overexpression.
Finally, we provide indirect evidence that the effect of melatonin on the cyclin D1 promoter is mediated by the c-jun and ATF-2 proteins, known to bind the minimal estrogen-sensitive cyclin D1 promoter element.
These findings establish for the first time a molecular link between melatonin and its effects on the cell cycle, providing at the same time a rationale for its use in adjuvant chemotherapy.
The Di Bella's Method: Use of Melatonin (together with others chemical compounds) in Breast Cancer:
- Complete objective response to biological therapy of plurifocal breast carcinoma;
See also:
- Official Web Site: The Di Bella Method;
- Melatonin use in cancer patients have started in 1974, when melatonin prepared according to Prof. Di Bella’s formulation [...]. For 11 days was administered to the patient, admitted to the general medical ward at the Maggiore-Pizzardi Hospital in Bologna, very slowly (over approx. 8 hours) and intravenously administered 1000 mg of melatonin for 11 days. During the course of each day, the patient was intravenously administered 4 saline drips of 500 ml, each containing ten 25 mg bottles of freeze-dried melatonin, lasting 2 hours, totaling 1000 mg per day. No other drug of any kind was administered in order to ascertain the effect of the MLT without interference [...]. From Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;
- About Melatonin - In vitro, review and in vivo publications;
- Publication: Melatonin anticancer effects: Review (from Di Bella's Foundation);
- Publication: Key aspects of melatonin physiology: 30 years of research (from Di Bella's Foundation);
- The Di Bella Method (A Fixed Part - Bromocriptine and/or Cabergoline);
- Prolactin inhibitors in oncology - In vitro, review and in vivo publications;
- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;
- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);
- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);
- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);
- Publication, 2019 Sep: Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes (from Di Bella's Foundation);
- Publication, 2020 Sep: Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives (from Di Bella's Foundation);
The Di Bella's Method: Use of Melatonin - together with others chemical compounds - in several Oncological Pathologies:
- Pleural Mesothelioma: clinical records on 11 patients treated with Di Bella's Method;
- Malignant pleural mesothelioma, stage T3-T4. Consideration of a case study;
- Neuroblastoma: Complete objective response to biological treatment;
- Large B-cells Non-Hodgkin's Lymphoma, Stage IV-AE: a Case Report;
- Non-Hodgkin's Lymphoma, Stage III-B-E: a Case Report;
- Oesophageal squamocellular carcinoma: a complete and objective response;
- Pancreatic Adenocarcinoma: clinical records on 17 patients treated with Di Bella's Method;