Journal of Physiology and Biochemistry (2019) 75:415–421 https://doi.org/10.1007/s13105-019-00697-1 REVIEW The emerging role of substance P/neurokinin-1 receptor signaling pathways in growth and development of tumor cells Hossein Javid1,2 & Fariba Mohammadi1,2 & Elnaz Zahiri1,2 & Seyed Isaac Hashemy1,3 Received: 24 March 2019 /Accepted: 23 July 2019 /Published online: 1 August 2019 # University of Navarra 2019 Abstract Tachykinins (TKs) include an evolutionarily conserved group of small bio-active peptides which possess a common carboxyl- terminal sequence, Phe-X-Gly-Leu-Met-NH2. TKs also have been shown to have implications in different steps of carcinogen- esis, such as angiogenesis, mitogenesis, metastasis, and other growth-related events. The biological actions of substance P (SP), as the most important member of the TK family, are mainly mediated through a G protein-coupled receptor named neurokinin-1 receptor (NK1R). More recently, it has become clear that SP/NK1R system is involved in the initiation and activation of signaling pathways involved in cancer development and progression. Therefore, SP may contribute to triggering a variety of effector mechanisms including protein synthesis and a number of transcription factors that modulate the expression of genes involved in these processes. The overwhelming insights into the blockage of NK1R using specific antagonists could suggest a therapeutic approach in cancer therapy. In this review, we focus on evidence supporting an association between the signaling pathways of the SP/NK1R system and cancer cell proliferation and development. Keywords Tachykinins . Substance P . Neurokinin-1 receptor . Signaling pathways . Cancer Introduction progression may contribute to develop novel diagnostic and therapeutic approaches for the detection and treatment of Cancer is a chronic disease that is caused by faulty genome cancers. surveillance and signal transduction mechanisms [17, 33]. Tachykinins (TKs) include an evolutionarily conserved Recently, researchers have shown that mutations in genes that family of small bio-active peptides including substance P encode different components of various signaling pathways (SP), neurokinin A (NKA), and B (NKB) [46]. The mamma- occur at high frequency in cancers [27, 56]. Therefore, under- lian TKs possess a common carboxyl-terminal sequence, rep- standing the underlying mechanisms involved in cancer resented by Phe-X-Gly-Leu-Met-NH2, where X is either a branched aliphatic or aromatic amino acid [53]. These pep- tides are widely distributed in mammalian peripheral and cen- Key points • Tachykinins have implications in different steps of tral nervous systems and participate in the regulation of phys- carcinogenesis. • SP/NK1R system activates signaling pathways involved in tumorigen- iological functions like inflammatory processes, hematopoie- esis. sis, wound healing, leukocyte trafficking, microvasculature • The blockage of NK1R could suggest a therapeutic approach in cancer permeability, and cell survival [13, 31, 38, 44, 68]. TKs also therapy. have been shown to have implications in different steps of carcinogenesis, such as angiogenesis, mitogenesis, metastasis, * Seyed Isaac Hashemy and other growth-related events [8, 45]. [email protected] SP, as the most important member of the mammalian TK 1 Department of Clinical Biochemistry, Faculty of Medicine, Mashhad peptides, is derived from a single preprotachykinin A gene. University of Medical Sciences, Mashhad, Iran The biological functions of SP are mainly mediated through 2 Faculty of Medicine, Mashhad University of Medical Sciences, a G protein-coupled receptor (GPCR) named neurokinin-1 Mashhad, Iran receptor (NK1R) [36, 57]. It has been identified that both SP 3 Surgical Oncology Research Center, Mashhad University of Medical and NK1R are overexpressed in some cancer cells including Sciences, Mashhad, Iran breast, ovarian, pancreas, thyroid, prostate, glioblastoma, and 416 Javid et al. astrocytoma [4, 7, 9, 22, 39, 44]. Additionally, the binding of (40 μM) exerts an anti-tumorigenic effect via impaired inter- SP to NK1R mediates a major tumor progression pathway action of Forkhead Box M1 protein with β-catenin that results through initiation and activation of phosphoinositide 3- in inhibiting canonical Wnt signaling pathway in human kinase (PI3K), mitogen-activated protein kinases (MAPKs), hepatoblastoma cell lines [21]. Taken together, these results and other signaling pathways. Therefore, SP may contribute to conclusively suggest that pharmacological inhibition of triggering a variety of effector mechanisms including protein NK1R is detected as a promising therapeutic target in reduc- synthesis and progression of the eukaryotic cell cycle and a ing tumor growth in many types of cancer. 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 Tachykinins and MAPK signaling pathway effect on the pathogenesis of cancer progression are summa- rized. Understanding this can lead to a more effective thera- Mitogen-activated protein kinase (MAPK) cascades are ubiq- peutic approach or improve diagnostic procedures that are uitous and well-defined signal transduction modules found in used for cancer therapy/diagnosis. eukaryotic cells which play crucial roles in regulating various essential cellular processes including migration, proliferation, differentiation, and programmed cell death. Activation of Tachykinins and canonical Wnt signaling MAPKs occurs through dual phosphorylation of both regula- transduction pathway tory threonine and tyrosine residues, in response to a wide variety of extracellular signals including growth, hormones, The canonical Wnt signaling cascade is an important transduc- neurotrophic factors, and cytokines. tion pathway that regulates cell survival, proliferation, progres- Phosphorylated forms of ERK and p38 are two major com- sion, and metastasis through the activation of β-catenin [47, 49]. ponents of the MAPK family, which have been found to par- There are also several reports that Wnt ligands (such as Wnt 1, ticipate in tumor invasiveness and progression (summarized in Wnt 2, and Wnt 3a) are a large family of secreted glycoproteins Fig. 1)[10, 48, 51]. In support of a critical role of NK1R in that are cysteine-rich and highly hydrophobic. Wnts are pro- tumor differentiation, the data presented by Yamaguchi et al. duced as precursor proteins that contain a short N-terminal signal indicated that NK1R is required for the induction of c-Myc sequence and a mature segment that varies in length from ap- protein expression and cell growth through the activation of proximately 320 to 400 amino acids [19, 58, 64]. Accordingly, in the ERK1/2 pathway in human astrocytoma cells [61]. In line the absence of Wnt ligands, β-catenin is targeted for degradation with this, another in vitro study revealed that administration of through the interaction with Axin, adenomatous polyposis coli rottlerin (20 μM) and PP2 (20 μM), a protein kinase C delta (APC), and the protein kinase GSK-3. On the other hand, when inhibitor and sarcoma kinase (Src) inhibitor respectively, could cells are stimulated by Wnts, the degradation complex is disso- attenuate the SP-dependent ERK1/2 phosphorylation and there- ciated and β-catenin translocates to the nucleus. It results in β- by inhibiting the growth of human glioblastoma cells. These catenin accumulation and association with members of the lym- results clearly suggest that Src and PKC delta are candidate phoid enhancer-binding factor 1/T cell-specific transcription fac- molecules that serve as signal transducers between SP stimuli tor (LEF/TCF) protein family, leading to increased expression of and ERK1/2 activation in human glioblastoma cells [62]. several genes involved in cell proliferation including cyclin D1 Beta-arrestin1 (ARRB1) is a scaffold protein that contrib- and c-Myc (summarized in Fig. 1)[26, 29]. utes to GPCR desensitization and has also been associated Several studies have been published to report a cross talk with NK1R-mediated SP actions in tumor cell proliferation between administration of NK1R antagonist and the suppres- (summarized in Fig. 1)[16, 42, 66]. For example, Zhang sion of the Wnt signaling pathway (summarized in Fig. 1)[21, et al. found that ARRB1 knockdown could induce apoptosis 67]. For instance, Garnier et al. reported that the administra- and G2/M cell cycle arrest via suppressing the ERK1/2 and tion of aprepitant (< 40 μM), as a highly selective human Akt–NK1R interaction in glioblastoma cells [66]. NK1R antagonist, downregulates Wnt pathway-associated Matrix metalloproteinases (MMPs) are a major group of proteins including cyclin D1, c-Myc, and LEF-1, which there- degradative enzymes that act as effectors of extracellular ma- by leads to G2 cell cycle arrest and apoptosis in colon cancer trix invasion and metastasis in cancer cells. In line with this, Li cell lines [14]. Similarly, Niu et al. indicated that the admin- et al. showed that SP (< 1000 nM for 60 min) induces MMP-2 istration of another NK1R antagonist called NKP608 (10 μM and MMP-14 expression through enhanced activation of for 24 h) has the potential to reduce colorectal cancer cell ERK1/2, JNK, and Akt signaling pathways, thereby leading invasion and migration through blocking the ability of to breast cancer cell proliferation and invasion [25]. Moreover, Wnt3a to stimulate cyclin D1, β-catenin, and vascular endo- another study indicated