Research ArticleResearch Article

GPCR-CARMA3-NF-kappaB Signaling Axis: A Novel Drug Target for Cancer Therapy

Ji-yuan SUN
Clinical Oncology and Cancer Research June 2010, 7 (3) 159-168; DOI: https://doi.org/10.1007/s11805-010-0512-1

Abstract

G protein-coupled receptors (GPCRs) play pivotal roles in regulating various cellular functions. It has been well established that GPCR activates NF-κB and aberrant regulation of GPCR-NF-κB signaling axis leads to cancers. However, how GPCRs induce NF-κB activation remains largely elusive. Recently, it has been shown that a novel scaffold protein, CARMA3, is indispensable in GPCR-induced NF-κB activation. In CARMA3-deficient mouse embryonic fibroblast cells, some GPCR ligand-, like lysophosphatidic acid (LPA), induced NF-κB activation is completely abolished. Mechanistically, upon GPCR activation, CARMA3 is linked to the membrane by β-arrestin 2 and phosphorylated by some PKC isoform. Phosphorylation of CARMA3 unfolds its steric structure and recruits its downstream effectors, which in turn activate the IKK complex and NF-κB. Interestingly, GPCR (LPA)-CARMA3-NF-κB signaling axis also exists in ovarian cancer cells, and knockdown of CARMA3 results in attenuation of ovarian cancer migration and invasion, suggesting a novel target for cancer therapy. In this review, we summarize the biology of CARMA3, discuss the GPCR (LPA)-CARMA3-NF-κB signaling axis in ovarian cancer and speculate its potential role in other types of cancers. With a strongly increasing tendency to identify more LPA-like ligands, such as endothelin-1 and angiotensin II, which also activate NF-κB through CARMA3 and contribute to myriad diseases, GPCR-CARMA3-NF-κB signaling axis is emerging as a novel drug target for various types of cancer and other myriad diseases.

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Introduction

G protein-coupled receptors (GRCRs) are the largest cell surface receptor. Up to 2% of the human genome encodes GPCRs[1]. GPCRs are virtually expressed everywhere throughout the body, including the central nervous system, cardiovascular system, gastrointestinal tract, skeletomuscular system, urogenital system, reproductive system, and almost all other organs controlled by the autonomic nervous system[2]. GPCRs are activated by a diverse range of ligands, and play critical roles in physiology. They are involved in almost all types of stimulus-response pathways, and are important targets of 40% to 50% of modern medicinal drugs[3].

GPCRs signal through heterotrimeric G proteins (Gα, Gβ, Gγ) or β-arrestins[4,5]. G proteins are heterotrimeric G proteins, including 18 α subunits that are classified into 4 groups (Gs, Gi, Gq, G12/13), 12 β subunits, and 5 γ subunits[6]. These G proteins independently or cooperatively activate their downstream signaling reactions[6]. β-arrestins also function to relay GPCR-induced signals rather than simply desensitize the signals[7]. Upon activation, GPCRs activate numerous downstream effectors. One important target is nuclear factor kappa B (NF-κB).

NF-κB was first identified as a transcription factor of immunoglobulin κ light chain in B-cells and characterized for its important roles in the immune system[8]. Now, it has been revealed that NF-κB is ubiquitously expressed in all cell types, and has prominent roles in tumor progression, neural diseases, heart diseases, and immune diseases[8-12]. NF-κB has 5 members: p50, p52, RelA (p65), RelB, and c-Rel[8]. In resting cells, all members form homo- or heterodimers, and are sequestered in the cytoplasm through coupling to the inhibitor of κB (IκB) proteins, such as IκBα[13]. IκB masks the nuclear localization signal of NF-κB, and inhibits its function.

NF-κB is activated by the classical pathway or the alternative pathway[8]. Most receptors, like T-cell receptor (TCR) and B-cell receptor (BCR)[8], activate NF-κB through the classical pathway. Only a small number of receptors activate NF-κB through the alternative pathway[8,14]. Upon receptor activation, downstream adapters bind to these receptors and recruit kinases to activate the IκB kinase (IKK) complex[15,16]. IKK is comprised of IKKα, IKKβ, and IKKγ (NEMO) in the classical pathway and IKKα dimer in the alternative pathway. The IKK complex directly phosphorylates IκBα at serines 32 and 36, leading to subsequent IκBα polyubiquitination by the E3 ubiquitin ligase[8]. IκBα is then degraded by the 26S proteasome, and the NF-κB dimer is released and translocated into the nucleus, thereby transactivating their target genes[17].

While NF-κB has been discovered for 30 years and its signaling pathways under many receptors have already been delineated, how NF-κB is activated under G protein-coupled receptors remains largely unknown. Recently, a significant clue to this mystery has been revealed with the identification of a novel scaffold protein, CARMA3, which plays a crucial role in GPCR-induced NF-κB activation.

CARMA protein family

Structure

CARMA proteins are caspase recruitment domain (CARD)-containing members of the membrane associated guanylate kinase (MAUGK) family (Fig. 1). The CARMA protein family has 3 members: CARMA1, CARMA2, and CARMA3. Each member shares similar structures: an N-terminal CARD, followed by a coiled-coil domain (CC), a linker region, a PDZ domain, a SH3 domain, and guanylate kinase (GUK)-like domain[18,19]. CARD domain is found in a variety of proteins, especially those involved in apoptosis and inflammation. This domain is comprised of 6-7 anti-parallel α helices with a hydrophobic core and a hydrophilic outer surface. It mediates the interaction of larger protein complex by association with different individual CARD domains[20-22]. CC mediates dimerization[23]. The linker region contains critical phosphorylation sites[24]. Upon phosphorylation of the linker region, CARMA proteins are activated, unfold its structure, and recruit downstream molecules. PDZ domain, SH3 domain, and GUK domain, are membrane-associated domains. They all act in membrane localization. Therefore, they are also named as membrane associated GUK (MAGUK) domain[25]. Interestingly, although the structure of GUK domain is similar to guanylate kinase, it does not have any kinase activity.

Fig. 1.
Fig. 1.

CARMA protein family. The CARMA protein family has 3 members, CARMA1, CARMA2, and CARMA3. Each member shares similar structures: an N-terminal CARD, followed by a coiled-coil domain, a linker region, a PDZ domain, a SH3 domain, and GUK-like domain. Although all CARMA protein members share similar structures, they are transcribed by specific genes, and expressed in different tissues. Specifically, CARMA1 is predominantly expressed in spleen, thymus, and peripheral blood leukocytes; CARMA2 is expressed only in placenta; CARMA3 is expressed in a broad range of tissues. It is especially highly expressed in liver, kidney, heart, and brain, but not in spleen, thymus, or peripheral blood lymphocytes.

Distribution

Although all CARMA protein members share similar structures, they are transcribed by distinct genes, and expressed in different tissues[18-19,26]. Specifically, CARMA1 is predominantly expressed in spleen, thymus, and peripheral blood leukocytes[18]; CARMA2 is expressed only in placenta[19]; CARMA3 is expressed in a broad range of tissues, and especially highly expressed in liver, kidney, heart, and brain, but not in spleen, thymus, or peripheral blood lymphocytes[26].

Function

Overexpression of CARMA proteins induce robust NF-κB activation[19,27]. However, the receptors which employ CARMA proteins to activate NF-κB remain unknown for a long time. Recently, it has been demonstrated that CARMA1 is required in TCR- and BCR-induced NF-κB activation[28-30]. We and other groups have also shown that CARMA3 is indispensable for some GPCR ligands (lysophosphatidic acid, endothelin-1, angiotensin II)-induced NF-κB activation[31,32]. Both CARMA1 and CARMA3 activate NF-κB by recruitment of same downstream molecules, Bcl10 (B-cell CLL-lymphoma 10), MALT1 (mucosa associated lymphoid tissue lymphoma translocation gene 1), and TRAF6 (tumor necrosis factor receptor-associated factor 6)[33-35]. Bcl10 and MALT1 are two indispensable proteins regarded to synergize in the NF-κB activation. TRAF6 is an E3 ubiquitin (Ub) ligase which catalyzes the formation of polyubiquitin chains on IKK and facilitates NF-κB activation[36,37]. Overexpression of CARMA2 also activates NF-κB. However, because CARMA2 is only expressed in placental tissue, the function of CARMA2 remains elusive.

Mechanism of Activation

Upon receptor activation, CARMA proteins are recruited to the membrane-proximal region of the receptors by adaptor proteins whereby they can be further phosphorylated by specific protein kinase C (PKC) isoforms, resulting in activation and recruitment of downstream effectors. In T-cells, an adaptor protein, the adhesion- and degranulation-promoting adaptor protein (ADAP) links CARMA1 to the membrane-proximal region of TCR, and facilitates its phosphorylation and activation by PKCθ[38]. In ADAP-deficient T-cells, TCR-stimulated assembly of the CARMA1-Bcl10-MALT1 (CBM) complex and NF-κB activation is substantially impaired[38]. Upon GPCR activation, CARMA3 is linked to the GPCR by β-arrestin 2. In β-arrestin 2-deficient mouse embryonic fibroblast cells, the GPCR ligand, lysophosphatidic acid-, induced NF-κB activation is completely abolished. Although β-arrestins have also been reported to inhibit GPCR-induced NF-κB activation[39,40], we propose that the phosphorylation status of β-arrestin 2 may critically regulate and determine its function in NF-κB activation.

After CARMA proteins are linked to the receptor proximal region, PKC is engaged in phosphorylation of CARMA proteins. In T- and B-cells, PKCθ and PKCβ phosphorylate CARMA1 respectively and play indispensable roles in TCR- and BCR-induced NF-κB activation. In both pathways, PKCθ and PKCβ phosphorylate similar residues on the link region of CARMA1 and contribute to NF-κB activation[41,42]. PKC also functions in GPCR-induced NF-κB activation. Several study groups have revealed that PKCα or PKCδ may be required for GPCR-induced NF-κB activation[32,43]. It has been reported that PKCδ deficiency impairs LPA-induced NF-κB-dependent interleukin-8 (IL-8) secretion[44] and dominant-negative PKCα attenuates LPA-induced NF-κB activation substantially[45], which indicate that PKCδ and/or PKCα may be the key PKC isoform to phosphorylate and activate CARMA3.

Specifically, in response to TCR and BCR activation, PKCθ and PKCβ become activated to phosphorylate S552 and S564/S649/S657 on the CARMA1 linker region respectively. Mutations of these residues abolish TCR- or BCR-induced NF-κB activation[46,47]. Similar to CARMA1, some PKC isoforms are also proposed to activate NF-κB through CARMA3 under GPCR[31-32,45]. To explore which residue of CARMA3 is phosphorylated, we have demonstrated that the CARMA3 mutant S520A, an analogue of CARMA1 S552A, does not rescue TCR-induced NF-κB activation[47], however, wildtype CARMA3 does rescue TCR-induced NF-κB activation in CARMA1-deficient Jurkat T-cells. Therefore, it suggests that CARMA3 S520 may be the critical site for phosphorylation and activation of CARMA3.

Upon phosphorylation of CARMA proteins, it has been shown that both CARMA1 and CARMA3 contribute to NF-κB activation by regulating the activity of the IKK complex through IKK NEMO polyubiquitination[32,37]. Although previous reports have suggested that phosphorylation of IKKα/β indicates its activation, we have found that phosphorylation of IKKα/β is not sufficient to induce its kinase activity[32]. Only after both IKKα/β is phosphorylated and IKK NEMO is ubiquitinated, IKK is then activated and able to phosphorylate downstream IκBα[32,37]. In GPCR (LPA)-induced NF-κB signaling, IKKα/β phosphorylation is controlled by a PKC-dependent, but CARMA3-independent pathway, and IKK NEMO polyubiquitination is controlled by a CARMA3-dependent pathway (Fig. 2). Therefore, in CARMA3-deficient murine embryonic fibroblast (MEF) cells, IKKα/β phosphorylation is still intact, but IKK NEMO polyubiquitination is impaired. Consequently, IKK is not activated and is unable to phosphorylate IκBα[32,37]. Thus LPA-induced NF-κB activation is completely abolished[32,37].

Fig. 2.
Fig. 2.

The working model for CARMA3-dependent NF-κB activation in LPA or GPCR signaling pathways. GPCR (LPA)-induced NF-κB activation involves the recruitment of CARMA3 to the receptor, which leads to form the CARMA3-Bcl10-MALT1-TRAF6 complex, thereby resulting in polyubiquitination of the IKK complex. Meanwhile, a CARMA3-independent and PKC-dependent signal induce phosporylation of the IKK complex by an unknown kinase under GPCR. After IKK is both polyubiquitinated (NEMO) and phosphorylated (IKKα/β), IKK is then activated, leading to NF-κB activation. In the absence of CARMA3, GPCR (LPA)-induced polyunbiquitination of the IKK complex is defective, thereby resulting in defects of IKK and NF-κB activation.

GPCR-induced NF-κB signaling pathways in tumor progression

GPCR activates NF-κB, and NF-κB up-regulates the expressions of numerous genes in tumor proliferation, anti-apoptosis, angiogenesis, migration, invasion, and metastasis, e.g. Cyclin D1[48], bcl-2[49], vascular endothelial growth factor (VEGF)[50,51], cyclooxygenase-2 (COX-2)[52], matrix metalloproteinase-2 (MMP-2)[51], matrix metalloproteinase-9 (MMP-9)[51], urokinase plasminogen activator (uPA)[50-51,53], interleukin-6 (IL-6)[54], interleukin-8 (IL-8)[51,55], and growth-regulated oncogene α (Groα)[56-58]. So, sustained NF-κB activity has emerged as a hallmark of many human cancers[9] (Fig. 3).

Fig. 3.
Fig. 3.

The NF-κB signaling pathways in tumorigenesis and tumor progression.

NF-κB plays an important role in almost every aspect of tumor progression. NF-κB promotes tumor cell proliferation, angiogenesis, metastasis, and inhibits apoptosis. Some GPCR ligand, like LPA, induces NF-κB activation, and serves as a cancer diagnostic marker. CARMA3 is indispensable for GPCR (LPA)-induced NF-κB activation. To fully define GPCR (LPA)-induced NF-κB signaling events may help to discover new drug targets, and bring about profound significance in clinical therapies.

One typical GPCR ligand that activates NF-κB and leads to tumor progression is lysophosphatidic acid (LPA). LPA is a major active constituent of serum. It is a water-soluble phospholipid derivative from an intermediate in the intracellular metabolism[59] or produced extracellularly from lysophosphatidylcholine by phospholipase A1/A2, or autotaxin (ATX/lysophospholipase D)[59-61]. Autotaxin is a widely expressed extracellular exo-phosphodiesterase. It contributes to the synthesis of LPA and promotes tumor invasion and metastasis[62]. LPA activates NF-κB and exerts striking wide hormone- and growth factor-like effects, such as proliferation, apoptosis, differentiation, and chemotaxis[59]. Therefore, it comes as no surprise that LPA plays an important role in tumor progression and invasion.

For example, LPA contributes to ovarian cancer progression, and serves as an ovarian cancer diagnostic marker[63]. In 90% of ovarian cancer patients, the LPA level is significantly elevated[64]. Additionally, LPA receptors, LPA1, LPA2 and LPA3, are aberrantly expressed in ovarian cancer cells[59]. LPA activates NF-κB, and NF-κB transcriptionally up-regulates the expressions of many genes in ovarian cancer. Because many of these genes play critical roles in proliferation, proteolysis, angiogenesis, migration and metastasis, they promote ovarian cancer progression and spreading eventually. Inhibition of NF-κB activation is reported to down-regulate these gene expressions and attenuate the corresponding phenotypes. Therefore, a complete understanding of the molecular events about LPA-induced NF-κB signaling cascade will help to identify novel drug targets for cancer therapies.

On the molecular level, LPA or GPCR activates NF-κB through multiple pathways[6]. However, which pathway weighs more in relaying signals to NF-κB remains to be further explored. Upon ligand binding to receptors, G proteins, such as Gαq, Gαi, and Gα12/13, are all activated[59]. Gαq activates phospholipase C β (PLC β), which hydrolyze phosphatidylinositol (4,5)-bisphosphate (PIP2). With consequent production of diacylglycerol (DAG) and calcium released from endoplasm, PKC is activated[65], thereby leading to NF-κB activation. This pathway promotes cell survival. Meanwhile, Gαi activates PI3K-AKT and SOS-RAS-ERK pathways[66,67], which activate NF-κB and promote cell spreading, migration, invasion, and DNA synthesis. In addition, Gα12/13 activates NF-κB through G12/13-RHO-GEF-RHOA pathway, and contributes to contraction and cell rounding[68]. Moreover, Gαs stimulates cAMP production and activates protein kinase A (PKA), thereby inhibiting NF-κB activation eventually[69].

Recently, we have identified that CARMA3 is indispensable in GPCR-induced NF-κB activation in mouse embryonic fibroblast cells[70]. However, whether the GPCR-CARMA3-NF-κB signaling axis also exists in cancer cells and whether the same signaling axis contributes to tumorigenesis and tumor progression have not yet been thoroughly deciphered. Here, we would briefly summarize the role of GPCR-CARMA3-NF-κB signaling axis in ovarian cancer using LPA as an example and speculate its potential role in other types of cancers.

GPCR (LPA)-CARMA3-NF-κB signaling axis in cancers

Ovarian cancer

Ovarian cancer is among the top 4 cancers in the world. LPA is consistently raised in the ascites of ovarian cancer patients. Elevation of LPA activates NF-κB, and transactivates numerous NF-κB target genes, such as cyclin D1, VEGF, uPA, IL-6, IL-8, etc. All these genes play critical roles in tumor proliferation, angiogenesis, migration, invasion, and metastasis.

For example, Hu et al.[48] have demonstrated that LPA, at concentrations present in ascitic fluid, could directly promote ovarian tumor growth by increasing the level of cyclin D1, a key G1-phase checkpoint regulator, thereby resulting in cell proliferation. In addition, LPA stimulates the secretion of VEGF[71], and promotes ovarian cancer angiogenesis, migration and invasion[72]. Furthermore, LPA enhances the secretion of interleukin-6 (IL-6), a pleiotropic cytokine that is involved in ovarian carcinogenesis via Gi-PI3K-AKT-NF-κB pathway[54].

Recently, Li et al.[53] have shown that LPA-induced and NF-κB-mediated ovarian cancer migration and invasion partially depend on the expression of NF-κB target gene uPA. Mutation of NF-κB binding site on the region of uPA promoter results in over 80% reduction in LPA-induced activation of uPA promoter. Together with other data, they concluded that the Gi-Ras-Raf-NF-κB-uPA signaling cascade is responsible for LPA-induced ovarian cancer cell migration and invasion.

More recently, Mahanivong et al.[45] have demonstrated that the LPA-CARMA3-NF-κB signaling axis also exists in ovarian cancer. In this study, they have shown that CARMA3 nucleates the LPA-NF-κB signaling pathway. LPA-induced NF-κB activation and ovarian cancer cell migration and invasion are attenuated upon silencing CARMA3, Bcl10 and MALT1 with specific siRNAs. Mechanistically, they have identified that Ras-PKCα signaling cascade is involved and PKCα may phosphorylate CARMA3. Thus they delineated the whole GPCR-CARMA3-NF-κB signaling pathway in ovarian cancer cells.

Before the discovery of CARMA3, accumulating evidence has suggested that LPA-NF-κB signaling axis contributes to ovarian cancer tumorigenesis and progression, whereas the precise signaling components and mechanisms are not well defined. This study provides the first evidence that LPA-CARMA3-NF-κB signaling axis exists and plays important roles in ovarian cancer cell progression and provides novel targets for clinical therapy[45]. In addition, it also offers insights into other types of cancers.

Breast cancer

Breast cancer remains the most frequent malignant tumor among women worldwide[73]. LPA is also present at elevated levels in ascites of breast cancer patients[74]. According to the expression profiling of human breast cancers, ATX, LPA1, LPA2, and LPA3 are expressed in most tumors, with levels of LPA2 and LPA3 being increased in poorly differentiated breast cancers[75-77]. In LPA transgenic mice, it has been shown that a number of signaling pathways, such as NF-κB signaling cascade, have been dysregulated[78].

Although the existence and function of the LPA/CARMA3/NF-κB signaling axis in breast cancer tumorigenesis and progression have yet to be confirmed, the axis may be found in breast cancer cells because of the high conservation of signaling pathways in most cell types. In addition, accumulating evidence has suggested that aberrant expressions of LPA-induced NF-κB target genes promote breast cancer tumorigenesis and progression.

For example, aberrant expressions of ATX and LPA receptors are associated with increased IL-8 and VEGF in breast cancer patients[79-81]. In addition, IL-8 and VEGF are significantly elevated in LPA transgenic mice with mammary tumors[78]. Moreover, it has been observed that a small but consistent increase of plasma IL-8 and VEGF in transgenic mice precedes tumorigenesis[78]. Because both IL-8 and VEGF are LPA-induced NF-κB target genes, it is quite possible that CARMA3 is also engaged in this signaling cascade.

In addition, Hu et al.[82] and Ishdorj et al.[83] have shown that LPA protects breast cancer cells from radiation and chemotherapy, suggesting that LPA-induced NF-κB survival pathway may be involved. Meanwhile, Samadi et al.[84] have also demonstrated that LPA protects MCF-7 breast cancer cells against taxol-induced apoptosis and partially reverses the taxol-induced arrest in the G2-M phase of the cell cycle. Together, we could propose that LPA may function through the activation of NF-κB to achieve these effects, because the activation of NF-κB up-regulates cyclin D1 and bcl2 in cell survival and anti-apoptotic pathways, thereby resulting in the reversal of cell cycle arrest and antagonize the taxol-induced apoptosis. Consequently, LPA-CARMA3-NF-κB signaling axis may exist in breast cancer cells.

Moreover, several studies have demonstrated that LPA directly stimulates breast cancer osteoclast differentiation[85] and metastasis[86,87]. It is well established that NF-κB regulates osteoclast differentiation[88], and osteoclast differentiation leads to breast cancer bone metastasis and progression[85,89]. Therefore, it is possible that CARMA3 may also serve as an important signaling component in LPA-induced NF-κB-mediated breast cancer growth and metastasis.

Together, all these results suggest LPA-CARMA3-NF-κB signaling axis may exist in breast cancer tumorigenesis and progression. Elucidation of the molecular events by which LPA stimulates breast cancer cell proliferation, anti-apoptosis, angiogenesis and metastasis might provide a clue for the development of new therapeutic agents.

Colon cancer

Colon cancer is a leading cause with 655,000 deaths worldwide every year. It has been demonstrated that LPA1 is highly expressed in human colon carcinoma[90,91], and the absence of LPA2 attenuates cancer progression in vivo[92]. In colon cancer DLD1 and SW480 cells, LPA enhances cell migration, proliferation, adhesion, and the secretion of VEGF and IL-8[90,91]. In addition, Sun et al.[91] have revealed that the Ras/Raf-MAPK, G12/13-Rho-RhoA and PI3K-AKT/PKB signal pathways may be mechanistically involved. Together, it suggests that LPA-induced NF-κB activation may play a significant role in colon cancer progression, because both of these up-regulated gene expressions and signaling pathways are highly associated with NF-κB activation.

Interestingly, LPA also transactivates epidermal growth factor receptor (EGFR) to indirectly activate NF-κB and enhance IL-8 secretion. Shida et al.[93] and Mori et al.[94] have shown that LPA partially promotes colon cancer cell migration and progression via transactivation of EGFR. Inhibition of the phosphorylation of EGFR in colon cancer DLD1 cells reduces the IL-8 secretion by 33%. Since LPA-induced NF-κB activation is completely abolished in CARMA3 deficient mice, it suggests that both LPA-induced and EGFR transactivation-induced NF-κB activation is abolished. Therefore, in addition to functioning downstream of LPA, CARMA3 may also function between the transactivation process or downstream of EGFR directly. Further research is needed to investigate the detailed molecular events.

Prostate cancer

Prostate cancer is the most common form of cancer affecting men in the world. Compared with benign tissue, Guo et al.[95] have shown that the expression of LPA1 is significantly higher in prostate cancer specimens, and LPA1 relays Gαi-dependent signals to promote prostate cancer proliferation. In addition, Raj et al.[96] have shown that NF-κB is constitutively activated in prostate cancers, but not in benign prostate tissue. They have also found that lysophosphatidic acid promotes survival of prostate cancer PC-3 cells via activation of NF-κB. Moreover, Xie et al.[97] and Sivashanmugam et al.[98] have revealed that LPA generated by prostate cancer cells in response to mitogens may act as an autocrine mediator, and the LPA-regulated NF-κB-dependent IL-6 secretion is an important messenger linking stromal and prostate epithelial cells, being critical for the initiation and progression of prostate cancer.

Recently, Hao et al.[99] have demonstrated that LPA is an important regulator for prostate cancer cell invasion and contributes to the development of metastasis. Mechanistically, Hwang et al.[100] have revealed that RhoA and NF-κB play important roles in LPA-induced NF-κB activation and prostate cancer cell invasion, because both of the RhoA inhibitor and NF-κB inhibitor block LPA-induced prostate cancer invasion. Therefore, it points to a model that LPA stimulates RhoA and further activates NF-κB, which in turn results in increased prostate cancer cell invasion. Together, these studies suggest that LPA-CARMA3-NF-κB signaling pathway may also exist and promote prostate cancer progression. Deciphering the details of signaling events will offer a potential new therapeutic approach to improve the outcome of prostate cancer patients.

Lung cancer

Lung cancer is the leading cause of cancer deaths in women and men throughout the world. Yamada et al. have shown that lung cancers are developed in rats using N-nitrosobis (2-hydroxypropyl) amine (BHP). Further mechanism studies have revealed that LPA1 mutations were detected in 2 out of 12 adenomas (16.7%) and 7 out of 17 adenocarcinomas (41.2%), but not in 15 hyperplasias. These results suggest that mutations of LPA1 gene may be involved in the acquisition of growth advantage from adenomas to adenocarcinomas in lung carcinogenesis induced in rats by BHP[101].

In addition, Imamura et al.[102] have shown that the production of LPA in tumor cells seems critical for the invasion by human lung cancer MM1 or OC10 cells. Moreover, Xu et al.[103] have shown that LPA inhibitor causes lung cancer cells to regress and lose vascularity in engineered lung cancer xenograft tumors. Therefore, it also indicates a possible involvement of LPA-CARMA3-NF-κB signaling axis in lung cancer carcinogenesis and progression.

Perspective

GPCR-CARMA3-NF-κB signaling axis is a novel signaling pathway. GPCRs belong to a big family. There are more than 1000 GPCRs. Characterization of the role of CARMA3 in GPCR-induced NF-κB activation signaling pathway will help to delineate a holistic view on GPCR-induced NF-κB activation in tumor progression (ovarian, colon, prostate, breast, head and neck cancers, and Kaposi Sarcoma)[59,104], and other diseases, such as LPA- and NF-κB-induced ischemia reperfusion injury[105,106], and coronary artery diseases[106,107]. With a strongly increasing tendency to identify more LPA-like ligands, such as the recently identified endothelin-1 and angiotensin II, which also activate NF-κB through CARMA3 and contribute to myriad diseases, CARMA3 is expected to play critical roles in a broad range of physiological and pathological procedures.

Future research will define the molecular mechanisms regarding how GPCR, β-arrestin 2, CARMA3, PKC, and IKK induce NF-κB activation, and how this signaling axis induces NF-κB activation under other types of GPCRs or non-GPCR receptors. Also, we will investigate other novel signaling pathways that the GPCR-CARMA3-NF-κB signaling axis mediates, and the aberrant regulations of signaling cascades in diseases as well. Characterizing the roles and the mechanisms of GPCR-CARMA3-NF-κB signaling axis will help to discover new drug targets, and bring about profound significance in many diseases and therapies.

Conflict of interest statement

No potential conflicts of interest were disclosed.

  • Received June 1, 2010.
  • Accepted June 18, 2010.

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