Melatonergic index as a prognostic biomarker of reproductive organ cancers: correlations with metabolic parameters as well as clock genes PER1 and TIMELESS

Abstract

Cancers of the reproductive organs are often hard to be detected, and patients’ survival rate drops considerably even when the tumor is removed. Based on the fact that melatonin levels are significantly lower in cancer cells than that in the healthy cells, and this melatonin suppression remains during tumor progression, we have examined a simple two-gene-based melatonergic system [the indices of melatonin synthesis and metabolism (ASMT:CYP1A1, ASMT:CYP1A2, ASMT:CYP1B1)] as a prognostic factor for reproductive organ cancer survival rate. RNA-seq data from The Cancer Genome Atlas (TCGA) of seven types of human reproductive organ tumors (n = 3571 samples) were analyzed. By stratifying the set of index values into high vs low risk, we observed that patients with a high melatonergic index had improved survival rates for cervical, ovarian, and endometrial cancers. Patients at high-risk (low melatonergic index) showed a trend of diagnosis of breast, prostate, and testicular cancers at the younger age, while patients with cervical, ovarian, and endometrial cancers presented with higher tumor staging. The melatonergic indices, especially the ASMT:CYP1B1, positively correlated with the clock gene PER1 while negatively correlated with the clock gene TIMELESS in all reproductive organ cancers. We further analyzed the correlation between the expression profiles of the melatonin-synthesizing enzyme (ASMT gene) with metabolic enzyme-encoding genes. Notably, LDHA, PDK1, and PDHA1 showed a higher correlation in male and female reproductive organ tumors, while IDH1, SDHB, GLS, and ATP1A1 had a positive correlation in breast, testicular, and endometrial cancers. These results have provided a comprehensive evaluation of the melatonergic system in relation to the reproductive organ tumor microenvironment and identified promising gene signatures as potential biomarkers for cancer diagnostics, prognostics, and therapeutics.

Melatonin Reverses the Warburg-Type Metabolism and Reduces Mitochondrial Membrane Potential of Ovarian Cancer Cells Independent of MT1 Receptor Activation

“…Treatment of uterine endometrial cancer cells with melatonin halts tumor progression through SDH inhibition [ 44 ]. Moreover, we previously reported that female reproductive organ tumors exhibit a positive correlation of ASMT with OXPHOS-related enzymes including PDHA1 and SDHB [ 45 ]. Mitochondria have the machinery responsible for the conversion of redox energy into an electrochemical gradient and the production of ATP formed in ETC through ATP synthase [ 46 ].…”