Stokłosa Paulina, Borgström Anna, Kappel Sven, Peinelt Christine (2020), TRP Channels in Digestive Tract Cancers, in International Journal of Molecular Sciences
, 21(5), 1877-1877.
Kappel Sven, Stokłosa Paulina, Hauert Barbara, Ross‐Kaschitza Daniela, Borgström Anna, Baur Roland, Galván José A., Zlobec Inti, Peinelt Christine (2019), TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells, in Molecular Oncology
, 13(11), 2393-2405.
Colorectal cancer (CRC) is the third most common cancer and worldwide, roughly 1.36 million patients are diagnosed with CRC each year. As in other types of cancer, in CRC imbalances in store-operated Ca2+ entry (SOCE) contribute to several cancer hallmarks, functions such as increased proliferation, a reduced ability to induce cell death, and invasion. Our preliminary data demonstrate that in CRC cells intracellular Ca2+ activates transient receptor potential melastatin-4 channel (TRPM4) and that TRPM4 conducts large Na+ currents. TRPM4-mediated Na+ influx can depolarize the membrane potential, thereby decreasing the driving force for Ca2+ and thus reducing SOCE signals as a feedback mechanism. Our preliminary data show that TRPM4 is a negative regulator for SOCE in CRC cells. In CRC cells, TRPM4 expression levels seem to be impaired. Within this project, we aim to study the physiological and pathophysiological role of TRPM4 in CRC cells. We will test for TRPM4 expression levels in human CRC tissue slices. We plan to use cellular assays (proliferation, apoptosis and migration) to investigate the role of TRPM4 in CRC cells. With this we plan to test for TRPM4 as putative therapeutic target in CRC. In addition, we plan to determine the potential of different TRPM4 blockers that are currently being developed to alter cancer hallmark functions. In order to investigate the mechanism(s) that underlie(s) TRPM4’s role in cellular functions (modulation of SOCE, Na+ influx or protein-protein interaction), we plan different sets of experiments including Ca2+ and Na+ imaging assays and analysis of different TRPM4 constructs that either conduct Na+ (TRPM4WT) or Ca2+ (TRPM4Ca2+) and a dominant negative mutant (TRPM4D984A). Taken together, within our proposal we plan to investigate the role of TRPM4 in CRC and the regulation of TRPM4 as a versatile mechanism in cancer cells.