TRP proteins and cancer

doi:10.1016/j.cellsig.2006.08.012

Cellular Signalling

Volume 19, Issue 3, March 2007, Pages 617-624

https://doi.org/10.1016/j.cellsig.2006.08.012 Get rights and content

Abstract

Cancer is the second most common cause of death in western countries. It is therefore of fundamental importance to improve the treatment of patients with malignant tumors. This goal can only be achieved if we get closer insight in the various mechanisms leading to tumor formation. Significant progress in the understanding of carcinogenesis has been made during the last couple of years. Ion channels contribute to the regulation of cell proliferation which has initially been shown for K⁺ channels. Meanwhile, other ion channels such as Cl⁻, Na⁺ and Ca²⁺ channels seem to influence cellular function like growth, migration and invasion. In addition, cation channels of the transient receptor potential (TRP) superfamily are implicated in cancer formation. Most recent data concerning TRP vanilloid (TRPV) type 6, TRP melastatin (TRPM) type 1 and 8 channels and their relevance for common human cancer types will be highlighted in this review. Furthermore, TRP channel structure and function will be discussed in the light of their possible importance as prognostic markers and targets for drug discovery.

Introduction

Ion channels play a crucial role in a variety of physiological functions such as excitability, muscle contraction and hormone secretion (reviewed by [1]). In addition to these life supporting activities, ion channels are also associated with several diseases (reviewed by [2], [3]) including cancer (reviewed by [4], [5]). This relationship has been demonstrated mainly for K⁺ channels (reviewed by [6], [7], [8]) such as ether à go–go (EAG) K⁺ channels [9], [10], [11], [12], [13]. Several other ion channels seem to be associated to cell proliferation including Na⁺ (reviewed by [14]), Cl⁻channels [15], [16], cation channels [17], voltage-dependent Ca²⁺ channels [18], [19], [20] and store-operated Ca²⁺ current [21]. This review focuses on transient receptor potential (TRP) channels and their association to most common cancers. The role of TRP channels in diseases other than malignant tumors has been described elsewhere (reviewed by [22]) and is especially well characterised for mucolipidosis (reviewed by [23]), polycystic kidney disease (reviewed by [24]) and hypomagnesaemia with secondary hypocalcaemia (reviewed by [25]).

Section snippets

TRP superfamily

TRP channels were initially identified in Drosophila melanogaster and named after their role in phototransduction: Fruit flies carrying mutations in their TRP gene exhibited a transient voltage response of their photoreceptors to continuous light [26], [27], [28]. As a consequence of the decreased Ca²⁺ entry via TRP channels, Ca²⁺ dependent adaptation is disturbed. Thus, TRP deficient flies become blind when exposed to intense light (reviewed by [29], [30], [31], [32]).

The mammalian TRP

TRPC, TRPV and TRPM subfamilies

The mammalian TRPC proteins can be divided into three subgroups by sequence homology and functional similarities: C1/C4/C5, C3/C6/C7 and C2 (Fig. 1). They are most closely related to the Drosophila TRP protein. TRPC proteins function as receptor-operated cation channels and become activated by stimulation of G-protein-coupled receptors and receptor tyrosine kinases (reviewed by [36], [37]).

The TRPV channel subfamily has six members divided into two groups: V1/V2/V3/V4 and V5/V6 (Fig. 1). The

Cancer related TRP proteins

TRP proteins have diverse functional properties and profound effects on a variety of physiological and pathological conditions. Only TRP proteins which are associated with cancer will be addressed in this review. These are TRPV6 (Table 1), TRPM1 (Table 2) and TRPM8 (Table 3). Additional TRP channels have been proposed to be involved in tumor growth although the experimental evidences for this is limited [59], [60]. For instance, TRPM5 is related to cancer since its gene was identified on a

TRPV6

TRPV6 mRNA is overexpressed in prostate adenocarcinoma [63], [64]. In contrast, either no transcripts were detected in healthy prostate tissue and benign prostatic hyperplasia [63], [65] or only low expression levels were found [64]. In any case TRPV6 expression correlates with the tumor grade and aggressiveness as shown by in situ hybridisation of human biopsy specimens [64], [65]. Peng and coworkers showed significant higher expression levels in cancer specimens (n = 27) than in the benign

TRPM1

TRPM1 was identified in a differential display analysis of B-16 mouse melanoma cell lines [47]. Transcripts showed increased expression in poorly metastatic variants of this cell line (B-16-F1) versus highly metastatic cells (B-16-F10). Similarly in situ hybridisation of human specimens revealed high expression levels in benign nevi whereas primary melanoma showed a decreased expression and no transcripts were detected in metastatic melanoma [47]. Thus, the down regulation of TRPM1 transcript

TRPM8

The TRPM8 cDNA was initially cloned during a screen for mRNA up-regulated in prostate cancer [94]. It is not exclusively overexpressed in malignant tissue of the prostate but also in other primary cancers including melanoma, colorectal adenocarcinoma and breast carcinoma whereas mRNA was not or only minimally expressed in the corresponding non malignant tissue. No TRPM8 transcripts were detected by northern blot analysis in a wide variety of other organs such as skeletal muscle, uterus, colon,

Conclusions and perspectives

Proteins of the TRP superfamily such as TRPV6, TRPM1 and TRPM8 are associated with various cancers. Most studies show a correlation between mRNA expression levels and cancer progression. This has been done using human cell lines and specimens from patients. Due to the lack of selective antibodies very few data are available with respect to changes in protein expression. Interestingly, the correlations between mRNA expression levels of distinct TRP genes and tumor growth can be either positive

Acknowledgements

I would like to thank Professor Veit Flockerzi, Professor Adolfo Cavalié and Dr. Brigitte Held for reading the manuscript.

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TRPV6, a Ca²⁺-selective member of the transient receptor potential vanilloid (TRPV) family, plays a key role in extracellular calcium transport, calcium ion reuptake, and maintenance of a local low calcium environment. An increasing number of studies have shown that TRPV6 is involved in the regulation of various diseases. Notably, overexpression of TRPV6 is closely related to the occurrence of various cancers. Research confirmed that knocking down TRPV6 could effectively reduce the proliferation and invasiveness of tumors by mainly mediating the calcium signaling pathway. Hence, TRPV6 has become a promising new drug target for numerous tumor treatments. However, the development of TRPV6 inhibitors is still in the early stage, and the existing TRPV6 inhibitors have poor selectivity and off-target effects. In this review, we focus on summarizing and describing the structure characters, and mechanisms of existing TRPV6 inhibitors to provide new ideas and directions for the development of novel TRPV6 inhibitors.
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Angiogenesis is an essential physiological process in the growth and metastasis of primary tumors. Ca²⁺ signaling is crucial for tumor angiogenesis. The purpose of this study was to detect the potential role of Ca²⁺ permeable transient receptor potential vanilloid-3 (TRPV3) in the angiogenesis of non-small cell lung cancer (NSCLC).
Small interfering RNA was used to down-regulate TRPV3 expression in A549 cells. A laser scanning confocal microscope was used to examine intracellular calcium concentration ([Ca²⁺]i). Human umbilical vein endothelial cells (HUVECs) tube formation and migration assay, Western blot, MTT and ELISA were performed to detect the potential mechanisms of TRPV3 in tumor angiogenesis. A mouse tumor xenograft model was performed to expound the effects of TRPV3 on tumor cell growth.
Inhibition of TRPV3 reduced [Ca²⁺]i and protein expressions of VEGF and HIF-1α in A549 cells. Moreover, HIF-1α depletion decreased the secretion and expression of VEGF. Depletion of TRPV3 inhibited HUVECs proliferation, tube formation and migration induced by conditioned medium. And TRPV3 inhibition could decrease the volume of xenograft tumors and MVD of CD34⁺ cells. The expression levels of HIF-1α, VEGF and p-CaMKП in the xenograft tumors in RuR and siTRPV3 groups was reduced.
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Tumor metastasis is the primary cause of treatment failure and cancer-related deaths. Store-operated Ca²⁺ entry (SOCE), which is mediated by stromal interaction molecules (STIM) and ORAI proteins, has been implicated in the tumor invasion-metastasis cascade. Epithelial-mesenchymal transition (EMT) is a cellular program that enables tumor cells to acquire the capacities needed for migration and invasion and the formation of distal metastases. Tumor-associated angiogenesis contributes to metastasis because aberrantly developed vessels offer a path for tumor cell dissemination as well as supply sufficient nutrients for the metastatic colony to develop into metastasis. Recently, increasing evidence has indicated that SOCE alterations actively participate in the multi-step process of tumor metastasis. In addition, the dysregulated expression of STIM/ORAI has been reported to be a predictor of poor prognosis. Herein, we review the latest advances about the critical role of SOCE in the tumor metastasis cascade and the underlying regulatory mechanisms. We emphasize the contributions of SOCE to the EMT program, tumor cell migration and invasion, and angiogenesis. We further discuss the possibility of modulating SOCE or intervening in the downstream signaling pathways as a feasible targeting therapy for cancer treatment.
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TRP proteins and cancer

Abstract

Introduction

Section snippets

TRP superfamily

TRPC, TRPV and TRPM subfamilies

Cancer related TRP proteins

TRPV6

TRPM1

TRPM8

Conclusions and perspectives

Acknowledgements

Neurosci. Lett.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Pharmacol.

Am. J. Pathol.

J. Biol. Chem.

Cell Calcium

Trends Cell Biol.

Biochem. Biophys. Res. Commun.

Cell Calcium

Trends Pharmacol. Sci.

Trends Cell Biol.

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

Genomics

Mol. Cell

J. Biol. Chem.

Trends Pharmacol. Sci.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Lab. Invest.

J. Biol. Chem.

J. Biol. Chem.

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J. Biol. Chem.

Trends Pharmacol. Sci.

Biochem. Biophys. Res. Commun.

Human Pathol.

Genomics

Cell

Am. J. Pathol.

Sinaur

J. Membr. Biol.

J. Membr. Biol.

J. Membr. Biol.

J. Exp. Ther. Oncol.

Pflugers Arch.

EMBO J.

J. Physiol.

J. Membr. Biol.

Pflugers Arch.

J. Neurosci.

Glia