Melatonin suppresses cancer cell proliferation, DNA repair and expression of the oncogene TRIP13

TL;DR

Melatonin reduces cancer cell growth and DNA repair by lowering TRIP13 levels, suggesting a potential new treatment for lung cancer.

Contribution

The study reveals that melatonin suppresses TRIP13, DNA repair proteins, and cancer cell proliferation, offering a novel therapeutic strategy for NSCLC.

Findings

Melatonin downregulates TRIP13 in lung cancer cells, especially those with high TRIP13 expression.

Melatonin impairs DNA repair via homologous recombination and non-homologous end joining by inhibiting RAD51 and XRCC5.

Melatonin receptor 1B is crucial for TRIP13 downregulation, and melatonin reduces cell proliferation even in TRIP13-KO cells.

Abstract

Non-small cell lung cancer (NSCLC) continues to be a global health challenge, with limited treatment options and a high mortality rate. We recently found that lung cancer cells that express more genes that are typically restricted to the germline (germ cell cancer genes, GC genes) repair DNA double-strand breaks more rapidly, show higher rates of proliferation, and are more resistant to ionizing radiation, compared to cells that express fewer GC genes. Moreover, we found that the gene encoding TRIP13 (thyroid hormone receptor interactor 13) plays a significant role in this malignant phenotype. Here, we demonstrate that melatonin (MT), a hormone synthesized in the pineal gland, downregulates the expression of TRIP13, particularly in lung cancer cells with high expression of TRIP13. Moreover, this downregulation of TRIP13 by MT further inhibits the DNA repair proteins RAD51 and XRCC5, thereby impairing DNA repair via homologous recombination and non-homologous end joining. We further found that the melatonin receptor 1B (MTNR1B), rather than melatonin receptor 1 A (MTNR1A), is essential for MT mediated TRIP13 downregulation. Because we also found that treatment with MT still decreases cell proliferation of TRIP13-KO cells, combining MT with the TRIP13 inhibitor DCZ0415 would likely have an additive anti-proliferative therapeutic effect in the treatment of NSCLC.

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