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G protein-coupled receptors: novel targets for drug discovery in cancer

Key Points

  • G protein-coupled receptors (GPCRs) comprise the largest superfamily of receptors involved in transmembrane-initiated transduction pathways and are the most prominent family of validated pharmacological targets in biomedicine. Increasing evidence shows the role of GPCRs in mediating cancer cell proliferation, angiogenesis and metastasis.

  • GPCRs can crosstalk (or transactivate) with other cell surface receptors involved in cancer. For example, epidermal growth factor receptor (EGFR) signalling has a crucial role in regulating the growth, survival, migration and resistance to chemotherapies in numerous human malignancies through functional crosstalk with GPCRs. Major anticancer effects are obtained by targeting both EGFR and the endothelin A subtype receptor.

  • GPCRs and insulin/insulin-like growth factor 1 receptors cooperate in the regulation of many physiological functions as well as in the development of diverse tumours. The diabetes drug metformin prevents this cooperation; in epidemiological studies it reduced the risk of tumours in diabetic patients.

  • G protein-coupled receptor 30 (also known as G protein-coupled oestrogen receptor) mediates rapid effects induced by oestrogens and anti-oestrogens in boths normal and cancer cells. Overexpression of this receptor has been associated with negative clinical features and poor survival rates in patients with hormone-sensitive tumours.

  • The Gα12/13 subfamily of G proteins contributes to cancer development and progression, mainly through the activation of Rho family members which regulate cytoskeletal dynamics, transcriptional regulation, cell cycle progression and cell survival.

  • A GPCR named Smoothened activates the Hedgehog transduction pathway, which is implicated in the development of numerous malignancies. Accordingly, Smoothened antagonists elicit potent antitumour activity by inhibiting Hedgehog-dependent signalling.

  • Many human herpes viruses encode GPCRs which are implicated in virally induced oncogenesis. For example, the Kaposi-sarcoma-associated herpes virus encodes a GPCR that elicits transforming activity, anti-apoptotic effects, stimulation of cell growth and angiogenesis.

Abstract

G protein-coupled receptors (GPCRs) belong to a superfamily of cell surface signalling proteins that have a pivotal role in many physiological functions and in multiple diseases, including the development of cancer and cancer metastasis. Current drugs that target GPCRs — many of which have excellent therapeutic benefits — are directed towards only a few GPCR members. Therefore, huge efforts are currently underway to develop new GPCR-based drugs, particularly for cancer. We review recent findings that present unexpected opportunities to interfere with major tumorigenic signals by manipulating GPCR-mediated pathways. We also discuss current data regarding novel GPCR targets that may provide promising opportunities for drug discovery in cancer prevention and treatment.

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Figure 1: Selected transduction pathways involved in GPCR-mediated cancer signalling.
Figure 2: GPCR-induced transactivation of EGFR.
Figure 3: GPCRs and apoptotic pathways.

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Acknowledgements

This work was supported by funds from the Associazione Italiana Ricerca sul Cancro (project 8925/2010) and from the Ministero dell'Istruzione, dell'Università e della Ricerca (project PRIN 2008PK2WCW/2008).

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Correspondence to Marcello Maggiolini.

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Glossary

Angiogenesis

The growth of new blood vessels from pre-existing vessels. It is a fundamental step towards an aggressive tumour phenotype.

Metastasis

The ability of cancer cells to penetrate into lymphatic and blood vessels, circulate through the bloodstream and then invade and grow in normal tissues.

Transactivation

Stimulation of gene transcription by transcription factors that can bind to DNA.

Transformed cells

Cells that acquire the properties and behaviour of cancer cells.

Nontransformed cells

Cells that have regular features.

Epithelial-to-mesenchymal transition

A process characterized by the loss of cell adhesion and increased cell mobility, which can occur during embryonic development and in the malignant transformation of cells.

Focal adhesion kinase

A non-receptor tyrosine kinase that resides at the sites of integrin clustering, which are known as focal adhesions. It plays an important part in cell proliferation and migration, as well as in tumour growth, invasion and survival.

Paxillin

A focal adhesion-associated adaptor protein that facilitates the assembly of multi-protein complexes involved in the activation of signalling pathways that lead to cell migration and survival.

Amphiregulin

A member of the epidermal growth factor family that interacts with the epidermal growth factor receptor to regulate the growth of normal and transformed cells.

Cyclin D1

A member of the cyclin family that is required for cell cycle G1/S transition. Mutations, amplification and overexpression of cyclin D1 contribute to tumorigenesis and are observed frequently in various tumours.

Stroma

The supportive framework of an organ, gland or other structure, usually composed of connective tissue.

Anchorage independent proliferation

The proliferation of cells that are unattached to a substrate. Such proliferation can occur in cancer cells and contribute to metastasis.

Primary resistance

Lack of efficacy of a drug (or drugs) in patients who had never received treatment with that drug (or drugs).

Acquired resistance

A lack of efficacy of a drug (or drugs) that initially elicited a response.

Endothelial differentiation genes

Genes that encode G protein-coupled receptors for lysophosphatidic acid or the lysophospholipid mediator sphingosine 1-phosphate.

Diastereomer

An isomer that is a stereoisomer of a compound with two or more chiral centres and that is not a mirror image of another stereoisomer of the same compound.

μNeoplastic tissue

An abnormal mass of tissue that is generated by uncoordinated and excessive cell proliferation that persists after cessation of the stimuli.

Herpes viruses

A large family of DNA viruses that can infect and cause illness in humans.

Kaposi's sarcoma

Cancer characterized by numerous bluish-red nodules on the skin, the development of which is mainly caused by human herpes virus 8 (also known as Kaposi's sarcoma-associated herpes virus).

Burkitt's lymphoma

A non-Hodgkin's lymphoma (also called B cell lymphoma) that is associated with the Epstein–Barr virus.

Hodgkin's disease

A type of lymphoma that originates in lymph nodes and spreads to the spleen, liver and bone marrow.

β2-microglobulin

A component of major histocompatibility complex class I molecules that acts as an oncogenic factor capable of stimulating the growth and invasion of various types of tumour.

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Lappano, R., Maggiolini, M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov 10, 47–60 (2011). https://doi.org/10.1038/nrd3320

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