TRPM4 in Cancer-A New Potential Drug Target

Abstract

Transient receptor potential melastatin 4 (TRPM4) is widely expressed in various organs and associated with cardiovascular and immune diseases. Lately, the interest in studies on TRPM4 in cancer has increased. Thus far, TRPM4 has been investigated in diffuse large B-cell lymphoma, prostate, colorectal, liver, breast, urinary bladder, cervical, and endometrial cancer. In several types of cancer TRPM4 is overexpressed and contributes to cancer hallmark functions such as increased proliferation and migration and cell cycle shift. Hence, TRPM4 is a potential prognostic cancer marker and a promising anticancer drug target candidate. Currently, the underlying mechanism by which TRPM4 contributes to cancer hallmark functions is under investigation. TRPM4 is a Ca²⁺-activated monovalent cation channel, and its ion conductivity can decrease intracellular Ca²⁺ signaling. Furthermore, TRPM4 can interact with different partner proteins. However, the lack of potent and specific TRPM4 inhibitors has delayed the investigations of TRPM4. In this review, we summarize the potential mechanisms of action and discuss new small molecule TRPM4 inhibitors, as well as the TRPM4 antibody, M4P. Additionally, we provide an overview of TRPM4 in human cancer and discuss TRPM4 as a diagnostic marker and anticancer drug target.

Keywords: calcium; cancer; drug target; ion channel; migration; prognostic marker; proliferation.

Figure 1

Activation of TRPM4 and the regulation of Ca²⁺ entry. An increase in intracellular Ca²⁺ concentration activates TRPM4, which opens and conducts a large influx of Na⁺ ions. The positively charged Na⁺ ions then depolarize the plasma membrane and thereby inhibit store-operated Ca²⁺ entry (SOCE) via the Orai1 channel. The dysregulation of intracellular Ca²⁺ signaling is linked to several cancer hallmark functions, including increased proliferation, migration, invasion, and the inability to induce apoptosis. TRPM4 has several interaction partners that, in part, have been shown to modulate its functions, including SUR1 [102], 14-3-3 [102], KCTD5 [39], SUMO [16], TRPC3 [102], and subunits Glu2A and Glu2B, which are subunits of the NMDA receptor [100]. In addition, TRPM4 can be glycosylated and phosphorylated.

Figure 2

Summary of TRM4 expression levels in different cancer types compared to healthy control tissue (=: expression levels not changed, arrow: increased expression levels) [109].