Melatonin prevents deregulation of the sphingosine kinase/sphingosine 1-phosphate signaling pathway in a mouse model of diethylnitrosamine-induced hepatocellular carcinoma

Abstract

The sphingosine kinase (SphK)/sphingosine1-phosphate (S1P) pathway is involved in multiple biological processes, including carcinogenesis.

Melatonin shows beneficial effects in cell and animal models of hepatocellular carcinoma (HCC), but it is unknown if they are associated with the modulation of the SphK/S1P system, along with different downstream signaling pathways modified in cancer.

We investigated effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight i.p) once a week for 8 weeks. Melatonin was given at 5 or 10 mg/kg/day i.p. beginning four weeks after the onset of DEN administration and ending at the sacrifice time (10, 20, 30 or 40 weeks).

Melatonin alleviated the distortion of normal hepatic architecture, lowered the incidence of preneoplastic/ neoplastic lesions and inhibited the expression of proliferative/cell-cycle regulatory proteins (Ki67, PCNA, cyclin D1, cyclin E, CDK4 and CDK6). S1P levels and expression of SphK1, SphK2 and S1P receptors (S1PR1/S1PR3) were significantly elevated in DEN-treated mice. However, there was a decreased expression of S1P lyase.

These effects were significantly abrogated in a time- and dose-dependent manner by melatonin, which also increased S1PR2 expression. Following DEN treatment mice exhibited increased phosphorylation of PI3K, AKT, mTOR, STAT3, ERK and p38, and a higher expression of NF-κB p50 and p65 subunits.

Melatonin administration significantly inhibited those changes.

Data obtained suggest a contribution of the SphK/S1P system and related signaling pathways to the protective effects of melatonin in hepatocarcinogenesis.

About this publication.

See also:

- About Melatonin;

- Evaluation of the safety and efficacy of the first-line treatment with somatostatin combined with melatonisn, retinoids, vitamin D3, and low doses of cyclophosphamide in 20 cases of breast cancer: a preliminary report;

- The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 122 cases of breast cancer;

- Complete objective response to biological therapy of plurifocal breast carcinoma;

- Recurrent Glioblastoma Multiforme (grade IV – WHO 2007): a case of complete objective response achieved by means of the concomitant administration of Somatostatin and Octreotide – Retinoids – Vitamin E – Vitamin D3 – Vitamin C – Melatonin – D2 R agonists (Di Bella Method – DBM) associated with Temozolomide;

- Chronic Lymphocytic Leukemia: Long-Lasting Remission with Combination of Cyclophosphamide, Somatostatin, Bromocriptine, Retinoids, Melatonin, and ACTH;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status;

- Observations on the Report of a case of pulmonary adenocarcinoma with lymph node, hepatic and osseus metastasis;

- The Di Bella Method (DBM) in the treatment of prostate cancer: a preliminary retrospective study of 16 patients and a review of the literature.