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Review
. 2014 Apr:27:126-35.
doi: 10.1016/j.ceb.2014.01.005. Epub 2014 Feb 6.

"V体育ios版" Novel insights into G protein and G protein-coupled receptor signaling in cancer

Morgan O'Hayre  1 , Maria S Degese  1 , J Silvio Gutkind  2
Affiliations
Review

Novel insights into G protein and G protein-coupled receptor signaling in cancer

"VSports" Morgan O'Hayre et al. Curr Opin Cell Biol. 2014 Apr.

Abstract

G protein-coupled receptors (GPCRs) play a central role in signal transmission, thereby controlling many facets of cellular function. Overwhelming evidence now implicates GPCRs, G proteins and their downstream signaling targets in cancer initiation and progression, where they can influence aberrant cell growth and survival, largely through activation of AKT/mTOR, MAPKs, and Hippo signaling pathways. GPCRs also play critical roles in the invasion and metastasis of cancer cells via activation of Rho GTPases and cytoskeletal changes, and angiogenesis to supply the tumor with nutrients and provide routes for metastasis. Lastly, GPCRs contribute to the establishment and maintenance of a permissive tumor microenvironment. Understanding GPCR involvement in cancer malignancy may help identify novel therapeutic opportunities for cancer prevention and treatment VSports手机版. .

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Figures

Figure 1
Figure 1. Activation of growth and survival pathways by GPCRs
Stimulation of GPCRs results in the activation of multiple signaling pathways including second messenger generating systems, guanine nucleotide exchange factors (GEFs) for Ras and Rho GTPases, MAP kinases, PI3Ks, and their numerous downstream cytosolic and nuclear targets. This signaling network contributes to normal cell growth, survival, differentiation, and migration, but aberrant activation of GPCRs/G proteins and their downstream targets can result in tumor initiation, progression, and metastasis. In general, most mitogens acting on GPCRs stimulate Gαq/11, while others activate Gα12/13 and Gαi Gα subunits, which initiate intracellular signaling together with multiple pathways regulated by Gβγ subunits. In turn, these signaling routes converge in the nucleus to regulate the expression of growth promoting genes by the prolonged stimulation of transcription factors including c-FOS and c-JUN AP1 family members, YAP/TAZ, and c-MYC, among others. In parallel, activation of PI3K and AKT can induce cell proliferation by regulating cell cycle proteins, and promote cell survival through inactivation of pro-apoptotic proteins. AKT also activates an atypical kinase known as mTOR, which regulates protein synthesis, cell growth, and proliferation. In certain cancer cells, including colon cancer, activation of Gαs by COX-2 derived prostaglandins promotes cell proliferation by multiple mechanisms, including PKA-dependent regulation of multiple transcription factors and Gβs and Gβγ-initiated pathways controlling the accumulation of transcription factors such as β-catenin. See text for details.
Figure 2
Figure 2. Signaling by virally-encoded oncogenic GPCRs, and metastasis-related signaling pathways elicited by chemokine receptors
In general, chemokine receptors, such as CXCR4, drive cell migration primarily by acting on Gi and the stimulation of Gαi and Gβγ-initiated pathways controlling actin remodeling through PI3K and Rac GEFs, as well as the expression of pro-invasive gene programs. This is well exemplified by the role of CXCR4 in breast cancer metastasis. CXCR4 can also couple to G12/13 in basal-like breast cancer cells, where Gα13 protein expression is highly up-regulated, thereby driving metastasis in a Gα12/13-RhoA dependent manner. Similarly, LPA receptors and PAR-1 can activate Gα12/13-RhoA signaling in addition to Gαi. PI3K, Rac, and Rho signaling promotes the assembly of focal adhesions and actin polymerization important for inducing changes in cell shape and contraction, which are required for cell movement, thereby facilitating cancer cell migration, extravasation, and metastasis. Human oncogenic viruses, such as the Kaposi's sarcoma associated virus (KSHV/HHV8) express constitutively active GPCRs (vGPCRs) from their viral genome. Emerging evidence indicates that KSHV vGPCR initiates Kaposi's sarcoma, a highly angiogenic malignancy, by activating multiple intracellular signaling networks resulting in upregulation of expression and release of pro-angiogenic cytokines, such as VEGF, IL6, and IL8/CXCL8 and Gro-α/CXCL1, thus initiating paracrine neoplasia. Among these multiple pathways, the activation of AKT and mTOR through PI3Kγ represents a central pro-angiogenic and transforming mechanism deployed by KSHV-vGPCR, which has been successfully targeted in the clinic. The transforming effects of KSHV vGPCR also involves the activation of multiple MAPKs and their regulated transcription factors, including HIF-1α, AP-1, NF-kB, CREB, and NFAT transcription factors, all of which promote the expression and release of multiple KS-associated cytokines. Ultimately, KSHV vGPCR-expressing cells act in a paracrine fashion to stimulate the unrestricted growth of surrounding endothelial cells. See text for details.
Figure 3
Figure 3. GPCRs contribute to multiple facets of cancer progression
Cartoon depicting the involvement of GPCRs in cancer cell proliferation and survival, angiogenesis, invasion and metastasis, and inflammation and immune tolerance; short lists highlight some of the GPCRs involved in these processes.
See this image and copyright information in PMC

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