Introduction

Cancer is a chronic disease that is caused by faulty genome surveillance and signal transduction mechanisms [17, 33]. Recently, researchers have shown that mutations in genes that encode different components of various signaling pathways occur at high frequency in cancers [27, 56]. Therefore, understanding the underlying mechanisms involved in cancer progression may contribute to develop novel diagnostic and therapeutic approaches for the detection and treatment of cancers.

Tachykinins (TKs) include an evolutionarily conserved family of small bio-active peptides including substance P (SP), neurokinin A (NKA), and B (NKB) [46]. The mammalian TKs possess a common carboxyl-terminal sequence, represented by Phe-X-Gly-Leu-Met-NH2, where X is either a branched aliphatic or aromatic amino acid [53]. These peptides are widely distributed in mammalian peripheral and central nervous systems and participate in the regulation of physiological functions like inflammatory processes, hematopoiesis, wound healing, leukocyte trafficking, microvasculature permeability, and cell survival [13, 31, 38, 44, 68]. TKs also have been shown to have implications in different steps of carcinogenesis, such as angiogenesis, mitogenesis, metastasis, and other growth-related events [8, 45].

SP, as the most important member of the mammalian TK peptides, is derived from a single preprotachykinin A gene. The biological functions of SP are mainly mediated through a G protein-coupled receptor (GPCR) named neurokinin-1 receptor (NK1R) [36, 57]. It has been identified that both SP and NK1R are overexpressed in some cancer cells including breast, ovarian, pancreas, thyroid, prostate, glioblastoma, and astrocytoma [4, 7, 9, 22, 39, 44]. Additionally, the binding of SP to NK1R mediates a major tumor progression pathway through initiation and activation of phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinases (MAPKs), and other signaling pathways. Therefore, SP may contribute to triggering a variety of effector mechanisms including protein synthesis and progression of the eukaryotic cell cycle and a number of transcription factors that modulate the expression of genes involved in these processes [34, 37].

In this review, the signaling functions of SP/NK1R and its effect on the pathogenesis of cancer progression are summarized. Understanding this can lead to a more effective therapeutic approach or improve diagnostic procedures that are used for cancer therapy/diagnosis.

Tachykinins and canonical Wnt signaling transduction pathway

The canonical Wnt signaling cascade is an important transduction pathway that regulates cell survival, proliferation, progression, and metastasis through the activation of β-catenin [47, 49]. There are also several reports that Wnt ligands (such as Wnt 1, Wnt 2, and Wnt 3a) are a large family of secreted glycoproteins that are cysteine-rich and highly hydrophobic. Wnts are produced as precursor proteins that contain a short N-terminal signal sequence and a mature segment that varies in length from approximately 320 to 400 amino acids [19, 58, 64]. Accordingly, in the absence of Wnt ligands, β-catenin is targeted for degradation through the interaction with Axin, adenomatous polyposis coli (APC), and the protein kinase GSK-3. On the other hand, when cells are stimulated by Wnts, the degradation complex is dissociated and β-catenin translocates to the nucleus. It results in β-catenin accumulation and association with members of the lymphoid enhancer-binding factor 1/T cell-specific transcription factor (LEF/TCF) protein family, leading to increased expression of several genes involved in cell proliferation including cyclin D1 and c-Myc (summarized in Fig. 1) [26, 29].

Fig. 1
figure 1

The SP-NK1R signaling pathways. The SP-occupied neurokinin-1 receptor is a substrate for phosphorylation by G protein-coupled receptor kinase (GRK). Phosphorylation enhances the interaction of NK1R with β-arrestin, thereby translocating to the plasma membrane and mediating G protein uncoupling and receptor desensitization. SP bind to NK1R, followed by activation of Ras/Raf/MAPK and/or PI3K/Akt/mTOR. Raf, MAPK, Akt, and mTOR are classified as serine/threonine-specific protein kinases, which leads to stimulation of downstream proteins involved in the initiation of protein synthesis, resulting in cellular growth, invasion, and metastasis. In addition, administration of NK1R antagonist mediated suppression of the P38 MAPK signaling pathway, which results in NK-κB downregulation and consequent reduction of proinflammatory cytokines synthesis. On the other hand, Dickkopf1(DKK1) is an inhibitor of the canonical Wnt signaling pathway, which acts to interdict the interaction of LRP5/6 and Frizzled with Wnt ligands. Administration of NK1R antagonist is able to downregulate Wnt pathway-associated proteins through upregulation of Dkk1

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Several studies have been published to report a cross talk between administration of NK1R antagonist and the suppression of the Wnt signaling pathway (summarized in Fig. 1) [21, 67]. For instance, Garnier et al. reported that the administration of aprepitant (< 40 μM), as a highly selective human NK1R antagonist, downregulates Wnt pathway-associated proteins including cyclin D1, c-Myc, and LEF-1, which thereby leads to G2 cell cycle arrest and apoptosis in colon cancer cell lines [14]. Similarly, Niu et al. indicated that the administration of another NK1R antagonist called NKP608 (10 μM for 24 h) has the potential to reduce colorectal cancer cell invasion and migration through blocking the ability of Wnt3a to stimulate cyclin D1, β-catenin, and vascular endothelial growth factor (VEGF) signaling activity [40]. Consistently, another in vitro study showed that aprepitant (40 μM) exerts an anti-tumorigenic effect via impaired interaction of Forkhead Box M1 protein with β-catenin that results in inhibiting canonical Wnt signaling pathway in human hepatoblastoma cell lines [21]. Taken together, these results conclusively suggest that pharmacological inhibition of NK1R is detected as a promising therapeutic target in reducing tumor growth in many types of cancer.

Tachykinins and MAPK signaling pathway

Mitogen-activated protein kinase (MAPK) cascades are ubiquitous and well-defined signal transduction modules found in eukaryotic cells which play crucial roles in regulating various essential cellular processes including migration, proliferation, differentiation, and programmed cell death. Activation of MAPKs occurs through dual phosphorylation of both regulatory threonine and tyrosine residues, in response to a wide variety of extracellular signals including growth, hormones, neurotrophic factors, and cytokines.

Phosphorylated forms of ERK and p38 are two major components of the MAPK family, which have been found to participate in tumor invasiveness and progression (summarized in Fig. 1) [10, 48, 51]. In support of a critical role of NK1R in tumor differentiation, the data presented by Yamaguchi et al. indicated that NK1R is required for the induction of c-Myc protein expression and cell growth through the activation of the ERK1/2 pathway in human astrocytoma cells [61]. In line with this, another in vitro study revealed that administration of rottlerin (20 μM) and PP2 (20 μM), a protein kinase C delta inhibitor and sarcoma kinase (Src) inhibitor respectively, could attenuate the SP-dependent ERK1/2 phosphorylation and thereby inhibiting the growth of human glioblastoma cells. These results clearly suggest that Src and PKC delta are candidate molecules that serve as signal transducers between SP stimuli and ERK1/2 activation in human glioblastoma cells [62].

Beta-arrestin1 (ARRB1) is a scaffold protein that contributes to GPCR desensitization and has also been associated with NK1R-mediated SP actions in tumor cell proliferation (summarized in Fig. 1) [16, 42, 66]. For example, Zhang et al. found that ARRB1 knockdown could induce apoptosis and G2/M cell cycle arrest via suppressing the ERK1/2 and Akt–NK1R interaction in glioblastoma cells [66].

Matrix metalloproteinases (MMPs) are a major group of degradative enzymes that act as effectors of extracellular matrix invasion and metastasis in cancer cells. In line with this, Li et al. showed that SP (< 1000 nM for 60 min) induces MMP-2 and MMP-14 expression through enhanced activation of ERK1/2, JNK, and Akt signaling pathways, thereby leading to breast cancer cell proliferation and invasion [25]. Moreover, another study indicated that SP significantly enhanced the MMP-9 expression in endometrial adenocarcinoma, which in turn promotes tumor invasion, angiogenesis, and metastasis. Taken together, these data also suggest that inactivation of NK1R by L733.060, an NK1R antagonist, could reverse the SP-induced effects and may serve as an ideal target for novel therapeutic strategies designed to enhance the treatment of endometrial adenocarcinoma [28]. Human hemokinin-1 (hHK-1) is a member of the mammalian tachykinin family, which is overexpressed in tumor cells and has the greatest affinity for NK1R [59]. In line with this, an in vitro study indicated that hHK1 (< 1000 nM) could increase the MMP2 expression and then promote the melanoma cell migration through overactivation of the MAPK pathway [28]. These findings support the idea that NK1R is critical for cell proliferation and development, which may be developed a promising therapeutic strategy to improve clinical outcomes in the treatment of cancers.

The p38 MAPK is a signal transduction component that mediates various inflammatory cellular responses in human tumors (summarized in Fig. 1) [52]. Consistently, Fiebich et al. presented evidence showing that SP leads to induced accumulation of IL-6 in the human astrocytoma cell line by upregulating p38 MAPK signaling independent of NF-κB activation [12]. To further support the hypothesis that SP enhanced activation of key proinflammatory signal transduction pathways, Yamaguchi et al. showed that SP (100 nM) may also participate in IL-6 and IL-8 expression through p38 MAPK-mediated NF-κB activation in the human astrocytoma cell line. Moreover, the administration of ketamine (< 1 mM), as one of the NK1R antagonists, could reduce the SP-enhanced proinflammatory cytokines synthesis through inactivation of signaling effectors such as ERK, P38MAPK, and NF-κB involved in astrocytoma cell proliferation and metastasis [63]. These data clearly support the role of SP/NK1R system in regulating inflammatory processes and provide further evidence that the targeting NK1R by specific inhibitors is potential to serve as a leading agent for the development of therapeutic strategies against various malignancies.

Tachykinins and PI3K/AKT signaling pathway

The phosphoinositide 3-kinase (PI3K)/Akt signaling axis plays crucial roles in mediating both cell proliferation and development [30]. Recently, researchers have shown that the balance between PI3K/Akt and p53 pathways determines the cancer cells sensitivity to apoptosis [1, 5]. Furthermore, several studies provide new evidence of positive cross talk between the NK1R overexpression and PI3K/Akt-mediated cell proliferation and apoptosis resistance (summarized in Fig. 1) [2, 3].

For example, treating pre-B ALL cells with aprepitant at 20 μM for 1 day effectively reduces the phospho/total Akt ratio. These findings suggest that the inhibitory effect of aprepitant on Akt phosphorylation leads to an increased expression of P21 and P27 cell cycle regulatory proteins, which in turn induces G1/S cell cycle arrest and programmed cell death [3]. Consistent with the pro-apoptotic effect of NK1 receptor pharmacological inhibitors on cancer cells, Akazawa et al. demonstrated that 10 μM L-733,060, as a specific NK1R antagonist, could dissociate Akt-NK1R interaction, and results in dephosphorylation and inactivation of Akt. It has been shown that L-733,060 induces apoptotic cell death in glioblastomas [2]. These results clearly support the hypothesis that the blockage of NK1R with specific antagonists could counteract the SP-induced cell growth and may serve as a promising therapeutic target for cancer prevention.

Tachykinins and mTOR signaling pathway

The mammalian target of rapamycin (mTOR) signaling pathway is considered to be one of the most important molecular mechanisms of activating transducer proliferation signals in tumor cells [23, 24]. The mTOR kinase exists in two functionally separate multiprotein complexes, mTORC1 and mTORC2. The mTORC1 mediates the activation of p70 S6 kinase (p70S6k) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), whereas relatively little is known concerning the biological roles and functions of mTORC2. Although the signaling mechanisms that connect mTORC2 activity to malignancy are currently unclear, it has been shown that mTORC2 overactivation is associated with cell proliferation, survival, and differentiation [18, 41].

Rapamycin is a potent cytostatic agent which selectively inhibits the mTOR function and thereby blocks cell cycle progression at the G1/S phase [6]. Several lines of studies have shown that mTOR signaling axis is also activated by SP/NK1R in cancer cells (summarized in Fig. 1). Additionally, the blockage of mTOR activity by rapamycin could attenuate the phosphorylation of p70S6k and 4E-BP1 proteins, as well as the SP-induced cell proliferation and survival [21, 54]. For example, Sharif et al. indicated that SP (100 nM) enhances cell growth and metastasis by induced phosphorylation and activation of p70s6K and 4E-BP1 in human astrocytoma cell lines. These results also suggest that the use of rapamycin at low concentration (< 1 nM) is able to induce a gain-of-function complex with FK506 binding protein 12. This interaction significantly suppresses the SP-mediated phosphorylation of mTOR axis proteins and could be used as an effective therapeutic agent for the management of human malignancies [55].

Consistently, Ilmer et al. demonstrated that the administration of aprepitant (< 40 μM) attenuates mTORC1 activation and thereby reduces the phosphorylation of its downstream effectors including 4E-BP1/2, p70S6K, and S6, leading to a decrease in transcript synthesis of ribosomal proteins which promotes protein synthesis levels during hepatoblastoma cell proliferation [21]. It is becoming clear that the inhibition of NK1R with specific antagonists may contribute to the development of future anticancer strategies in cancer therapy.

Antitumor properties of NK1R antagonists against cancers

Major advances have been made towards identifying the specific agonists and antagonists for NK1R in order to provide the ideal tool for understanding the interactions in numerous biological and pathobiological processes. It has been reported that NK1R is capable of modifying the emotional behavior, stress, emesis, anxiety, depression, migraine, and cellular mechanisms of neurodegeneration in the central nervous system. In the peripheral nervous system, NK1R overexpression could lead to several inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), and rheumatoid arthritis (RA) [43].

Recently, several studies demonstrated that NK1R antagonists elicit an antitumor response in various human tumor cell lines, including acute myeloid leukemia, endometrial cancer, glioma, and neuroblastoma [15, 20, 32, 65]. It should be noted that such NK1R antagonists could reduce the basal level of Akt phosphorylation, which is also associated with enhanced caspase-3-dependent apoptotic cell death in human tumors [3]. In addition, tumor cell invasion is critical as it plays a major role and the first step in cancer metastasis which is the feature of malignant tumors resulting in dissemination of primary tumor cells to distant organs [11, 60]. In line with this, it has also recently been suggested that the same NK1R antagonists are able to suppress the SP-induced metastatic progression, cell migration, and invasion in various cancer cells. It seems this effect is mediated through the dissociation of the β-arrestin-containing complex and thereby the inactivation of the MAPK pathway [66]. Besides, acting as a highly potent antitumor agent, NK1R antagonists have an effective antiangiogenic action by suppressing hypoxia-inducible factor (HIF-1α) and VEGF expression as well as endothelial cell growth [35, 50]. Therefore, taken together, these findings clearly suggest that NK1R antagonists completely inhibit the SP-mediated proliferation and metastasis of tumor cells, which in turn could be considered as a novel therapeutic target for cancer treatment.

Conclusions and future perspectives

The findings described in this review article strongly support the hypothesis that a network formed by SP and NK1 receptor can exert cancer-enhancing effects in cellular and animal models. In fact, the SP/NK1R may act as an integrated system to regulate critical molecular mechanisms involved in tumor growth, differentiation, migration, and apoptosis resistance.

Pharmacological inhibition of NK1R might, therefore, be considered as a novel therapeutic procedure against malignancies. However, the carcinogenic activity of SP/NK1R signaling pathways have been intensively studied, and the underlying mechanisms of these functions are poorly understood. A deeper comprehension of NK1R signaling processes could lead to understanding or the addition of novel agents to regulate pathological responses and therefore improved management of cancers. More in vivo studies are required to illuminate the role of SP/NK1R system in cancer and their potential role in improving the chemotherapeutic effects of NK1R antagonist.