LMU researchers have discovered how the interaction between a key protein and an endolysosomal ion channel promotes tumor development in skin cancer.
Melanoma arising from pigment-producing cells known as melanocytes is the deadliest form of skin cancer. One of the main causes of melanoma is excessive exposure to ultraviolet light, from sunlight or other sources, which can trigger mutations that promote tumor formation. A team led by LMU pharmacologist Professor Christian Grimm (Walther Straub Institute for Pharmacology and Toxicology) and Dr Karin Bartel (Faculty of Chemistry and Pharmacy) has investigated the molecular mechanisms of tumorigenesis. As the researchers demonstrate, the interaction of two proteins, the TPC2 ion channel and the Rab7a enzyme, plays a decisive role, since they promote the growth and metastasis of melanoma.
Studies have shown that certain mutations that increase activity in the TPC2 ion channel are associated with light skin, blonde hair, and albinism. These traits make people particularly susceptible to melanoma, as their skin offers less protection against harmful ultraviolet radiation. In contrast, loss of TPC2 is associated with a decreased risk of melanoma. The ion channel controls the breakdown of important proteins in endolysosomes (cellular organelles involved in transport and degradation processes) and therefore influences signaling pathways that regulate tumor growth.
Molecular pathways that influence tumor progression.
Like TPC2, the Rab7a protein is an important regulator of the endolysosomal system. Furthermore, previous proteome analyzes had shown that Rab7a is a possible interaction partner of TPC2. Using modern methods such as endolysosomal patch clamp electrophysiology and measurement of lysosomal calcium release by fluorescence microscopy, the researchers established that there was indeed an interaction between Rab7a and TPC2 at the functional level, promoting the growth and invasiveness of melanoma cells. In contrast, pharmacological inhibition of Rab7a decreased TPC2 activity and, therefore, melanoma growth.
“Our results show that Rab7a, by amplifying the activity of TPC2, plays a key role in regulating tumor growth,” says Grimm. “Specifically, activation of TPC2 by Rab7a reduces the levels of a certain protein. This protein enhances the stability of a transcription factor that is a key regulator in melanocytes and melanomas and promotes their proliferation and survival.”
A particularly notable finding, according to the researchers, was that the effects of the interaction of Rab7a and TPC2 could be demonstrated in vivo. In mouse models with melanoma cells lacking Rab7a or TPC2, they found that tumor size and metastasis were greatly reduced. “The interaction between Rab7a and TPC2 could pave the way for new therapeutic strategies targeting specific signaling pathways that promote melanoma growth and metastasis,” Grimm concludes.