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.

Transcriptional Profiling of Tumorspheres Reveals TRPM4 as a Novel Stemness Regulator in Breast Cancer

“…associated with cancer stemness before, one of them being the TRPM4 gene, a member of the TRPM family of ion channels [15]. TRPM4 is known to be overexpressed in breast [16] and other types of cancer [47]. We confirmed these data by interrogating the Oncomine data base [48].…”

“…The TRPM4 channel is only permeable to monovalent cations, mostly to Na + and K + , upon activation by an increase in intracellular Ca 2 + [15]. Most interestingly to us, TRPM4 protein levels are increased in a variety of tumor types compared to healthy tissue, where it contributes to important cancer features, such as increased proliferation and migration and cell cycle shift (reviewed in [15,47]). Particularly in breast cancer, two recent studies showed that both the mRNA and protein levels of TRPM4 were upregulated in specimens from breast cancer patients [16,55].…”

“…As mentioned above, several studies have reported on the overexpression of TRPM4 in different types of cancer [52][53][54][55], and even though, its precise mechanism of action in tumors is currently unknown, it is already portrayed as a promising anticancer drug target [47].…”

TRP Channels Interactome as a Novel Therapeutic Target in Breast Cancer

“…TRPM4 is broadly expressed in several tissues (141) and modulates several cell functions, including insulin secretion (143), immune response (144), cell migration and contractility (145,146). TRPM4 also plays an important role in disease and several evidences has emerged linking the expression of TRPM4 with the increase of migration, invasion and proliferation of certain cancers, such as lymphoma (147), cervical (148), colorectal channel, prostate cancer (149)(150)(151) and others (152). Moreover, upregulation of this channel is associated with poor prognosis in large B cell lymphoma, breast cancer and endometrial carcinoma, while its overexpression increases the recurrence risk in prostate cancer (153)(154)(155)(156).…”

Transient Receptor Potential (TRP) Channels in Haematological Malignancies: An Update

“…However, some preliminary findings suggest that dysregulation of some members may be involved in lymphoma. In this regard, TRPM4 overexpression has been found in B-cell large lymphoma (DLBCL) [109].…”