Impaired redox adaptation through SLC38A5-dependent glutamine metabolism contributes to melatonin-mediated anoikis sensitivity and metastasis suppression in bone cancer
Abstract
Malignant bone cancer, primarily osteosarcoma and chondrosarcoma, are highly aggressive neoplasms originating from bone tissue and characterized by a strong propensity for lung metastasis.
Tumor cells evade anoikis through reactive oxygen species (ROS)-mediated redox homeostasis, which modulates signaling cascades that promote proliferation, survival, and metastatic invasion into distant sites.
Melatonin, synthesized primarily by the pineal gland, has been implicated in cancer prevention and therapy due to its inhibitory effects on bone cancer growth and progression.
Little is known about the mechanisms underlying anoikis resistance in bone cancer cells or whether melatonin can therapeutically modulate this process.
We demonstrated that glutamine metabolism is essential for bone cancer cells to maintain anoikis resistance. Melatonin treatment disrupted glutamine metabolism and altered redox homeostasis, as evidenced by increased ROS accumulation and reduced NADPH/NADP⁺ ratios under anchorage-independent conditions.
Notably, solute carrier family 38 member 5 (SLC38A5), a glutamine transporter, was identified as a critical regulator of bone cancer progression, with higher SLC38A5 expression correlating with poorer clinical outcomes.
Melatonin suppressed SLC38A5 expression and attenuated anoikis resistance through inhibition of the PI3K-Akt signaling pathway. Consistently, reduced SLC38A5 expression was associated with decreased lung metastasis in melatonin-treated groups in an orthotopic mouse model.
Collectively, our findings reveal a previously unrecognized role of melatonin in modulating glutamine-dependent redox balance and anoikis resistance in bone cancer.
This study highlights SLC38A5-mediated glutamine metabolism as a critical determinant of metastatic potential and supports melatonin and SLC38A5 as promising therapeutic targets for osteosarcoma and chondrosarcoma.
The Di Bella's Method: Use of Melatonin (since 1974), Somatostatin/Octreotide analogues and/or derivatives (since 1977), Retinoids (40mg per day Beta-Carotene, 10mg per day ATRA and 10mg per day Axerophthol palmitate), Vitamin D, Cabergoline and/or Bromocriptine with pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea (together with others chemical compounds) in Osteosarcoma and Lung Cancer (the dosage and administration schedule must be individualised for each patient):
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);
- 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, 2018 Sep: The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature (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 Method (A Fixed Part - Bromocriptine and/or Cabergoline);
- Prolactin inhibitors in oncology - In vitro, review and in vivo publications;
The Di Bella's Method: Use of Melatonin since 1974 and pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea - together with others chemical compounds: the dosage and administration schedule must be individualised for each patient - in several Oncological Pathologies:
- Complete objective response to biological therapy of plurifocal breast carcinoma;
- 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;