16P - Melatonin modulates energy metabolism and kinases signaling in ovarian cancer cells

Background

Ovarian cancer (OC) is the second gynecological malignancy among women and presents high rates of recurrence associated with chemoresistance. Tumor cells adjust their energy metabolism in favor of their rapid progression. Melatonin (Mel), a hormone produced and secreted by the pineal gland during darkness, has obvious anti-tumor activities. Therefore, we investigated the mechanistic role of Mel on energy metabolism in human OC cells (SKOV-3 and CAISMOV24 cells), with special focus on glycolytic metabolism in addition to cell signaling molecules.

Methods

Cell lines were treated with Mel at concentrations of 3.4 μM for SKOV-3 and 7 μM for CAISMOV24 based on the cell cytotoxicity (CC50) for 24 h; a luzindole-treated group was used to test the influence of melatonin receptors, MT1 and MT2. Protein levels of glycolytic enzymes were analyzed by western blot and kinase levels were measured by multiplex assay.

Results

Melatonin levels dropped by half in the OC cells. We observed a significant decline in the levels of HIF-1α, G6PDH, GAPDH, LDH, and PDH in OC cells treated with melatonin regardless of the presence of luzindole, thus proving its receptor-independent actions; conversely, the luzindole-exposed groups had an upregulation of these proteins. In regard to kinases signaling, SKOV-3 cells treated with melatonin had a reduction in the concentration of CREB, JNK, NF-kB, p-38, ERK1/2, Akt, p70s6k, STAT3, and STAT5, all of them associated with tumor growth, metastasis, and recruitment of oncostatic components. In the CAISMOV24 cells, these molecules were reduced after the combination of melatonin with luzindole.

Conclusions

These findings showed that melatonin potentially regulates energy-related processes in OC cells, thereby favoring the reversal of the Warburg effect, in addition to attenuating cell signaling involved with tumor progression.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Institute of Biosciences of Botucatu.

Funding

CAPES, FAPESP (grant number: 2021/12971-7), CNPq (304108/2020-0).

Disclosure

All authors have declared no conflicts of interest.