Primary brain tumors remain among the deadliest of all
cancers.
Glioma grade IV (
glioblastoma), the most common and malignant type of
brain cancer, is associated with a 5-year survival rate of < 5%.
Melatonin has been widely reported as an anticancer molecule, and we have recently demonstrated that the ability of
gliomas to synthesize and accumulate this
indolamine in the surrounding microenvironment negatively correlates with
tumor malignancy. However, our understanding of the specific effects mediated through the activation of
melatonin membrane receptors remains limited. Thus, here we investigated the specific roles of MT1 and MT2 in
gliomas and
medulloblastomas. Using the MT2 antagonist
DH97, we showed that MT1 activation has a negative impact on the proliferation of human
glioma and
medulloblastoma cell lines, while MT2 activation has an opposite effect. Accordingly,
gliomas have a decreased
mRNA expression of MT1 (also known as MTNR1A) and an increased
mRNA expression of MT2 (also known as MTNR1B) compared to the normal brain cortex. The MT1/MT2 expression ratio negatively correlates with the expression of cell cycle-related genes and is a positive prognostic factor in
gliomas. Notably, we showed that functional selective drugs that simultaneously activate MT1 and inhibit MT2 exert robust anti-
tumor effects in vitro and in vivo, downregulating the expression of cell cycle and energy metabolism genes in
glioma stem-like cells. Overall, we provided the first evidence regarding the differential roles of MT1 and MT2 in
brain tumor progression, highlighting their relevance as druggable targets. KEY MESSAGES: • MT1 impairs while MT2 promotes the proliferation of
glioma and
medulloblastoma cell lines. •
Gliomas have a decreased expression of MT1 and an increased expression of MT2 compared to normal brain cortex. •
Tumors with a high MT1/MT2 expression ratio have significantly better survival rates. • Functional selective drugs that simultaneously activate MT1 and inhibit MT2 downregulate the expression of cell cycle and energy metabolism genes in
glioma stem-like cells and exert robust anti-
tumor effects in vivo.