New insight into the role of substance P/neurokinin‐1 receptor system in breast cancer progression and its crosstalk with <scp>microRNAs</scp>

Ebrahimi, Safieh; Javid, Hossein; Alaei, Amin; Hashemy, Seyed Isaac

doi:10.1111/cge.13750

Cited by 30 publications

(15 citation statements)

References 82 publications

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“…Since REST is downregulated in breast cancer, this results in an increased intratumoral SP-level. Considering the antitumoral effects of SP at lower levels, it has been proposed that intact SP stimulates tumorigenesis, while its bioactive fragments resulting from enzymatic hydrolysis can suppress tumor growth (54,55). While capsaicin-sensitive afferents are a pivotal source of CGRP, expression of this vasoactive neuropeptide was also not significantly lower in desensitized animals.…”

Section: Discussionmentioning

confidence: 99%

Desensitization of Capsaicin-Sensitive Afferents Accelerates Early Tumor Growth via Increased Vascular Leakage in a Murine Model of Triple Negative Breast Cancer

et al. 2021

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There is growing interest in the role of nerve-driven mechanisms in tumorigenesis and tumor growth. Capsaicin-sensitive afferents have been previously shown to possess antitumoral and immune-regulatory properties, the mechanism of which is currently poorly understood. In this study, we have assessed the role of these terminals in the triple negative 4T1 orthotopic mouse model of breast cancer. The ultrapotent capsaicin-analogue resiniferatoxin (RTX) was used for the selective, systemic desensitization of capsaicin-sensitive afferents. Growth and viability of orthotopically implanted 4T1 tumors were measured by caliper, in vivo MRI, and bioluminescence imaging, while tumor vascularity and protease enzyme activity were assessed using fluorescent in vivo imaging. The levels of the neuropeptides Calcitonin Gene-Related Peptide (CGRP), Substance P (SP), and somatostatin were measured from tumor tissue homogenates using radioimmunoassay, while tumor structure and peritumoral inflammation were evaluated by conventional use of CD31, CD45 and CD3 immunohistology. RTX-pretreated mice demonstrated facilitated tumor growth in the early phase measured using a caliper, which was coupled with increased tumor vascular leakage demonstrated using fluorescent vascular imaging. The tumor size difference dissipated by day seven. The MRI tumor volume was similar, while the intratumoral protease enzyme activity measured by fluorescence imaging was also comparable in RTX-pretreated and non-pretreated animals. Tumor viability or immunohistopathological profile was measured using CD3, CD31, and CD45 stains and did not differ significantly from the non-pretreated control group. Intratumoral somatostatin, CGRP, and SP levels were similar in both groups. Our results underscore the beneficial, antitumoral properties of capsaicin sensitive nerve terminals in this aggressive model of breast cancer, which is presumed to be due to the inhibition of tumor vascular bed disruption. The absence of any difference in intratumoral neuropeptide levels indicates non-neural sources playing a substantial part in their expression.

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Section: Discussionmentioning

confidence: 99%

Desensitization of Capsaicin-Sensitive Afferents Accelerates Early Tumor Growth via Increased Vascular Leakage in a Murine Model of Triple Negative Breast Cancer

et al. 2021

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“…Several studies have recently demonstrated that SP induces a series of signaling pathways through NK1R that mediate cellular excitability in several human tumor cells. It has important roles in forming and spreading various tumor cells via migration, angiogenesis, and metastasis [11][12][13][14][15][16]. is is important since the prevention of metastasis is a major goal in treating tumors.…”

Section: Introductionmentioning

confidence: 99%

The Effect of SP/NK1R on the Expression and Activity of Catalase and Superoxide Dismutase in Glioblastoma Cancer Cells

Korfi

Javid

Darban

et al. 2021

Biochemistry Research International

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Introduction. Glioblastoma is the most malignant brain tumor with different therapeutic protocols, including surgery, radiotherapy, and chemotherapy. Substance P (SP), a peptide released by sensory nerves, increases cellular excitability by activating the neurokinin-1 receptor (NK1R) in several human tumor cells. Aprepitant is a potent and long-lasting NK1R antagonist, considered a new agent for inhibiting proliferation and induction of apoptosis in malignant cells. This study aimed to evaluate the effects of the SP/NK1R system on the expression and activity of catalase and superoxide dismutase (SOD) in the glioblastoma U87 cancer cell line. Methods. Cytotoxicity was measured by the resazurin test, 24 hours after treatment, with increasing aprepitant concentrations. The production of reactive oxygen species (ROS) was also measured 24 hours after treatment with SP and aprepitant. Enzymes activity of catalase and SOD was measured using the corresponding assay kits. Real-time PCR also measured their expression. Results. Aprepitant significantly reduced the viability of U87 cells in a concentration-dependent manner. ROS production was significantly reduced, and the activity of catalase and SOD increased after treatment with aprepitant. The expression of catalase and SOD enzymes also increased significantly in the presence of aprepitant. Conclusion. The present study showed that aprepitant inhibited SP’s oxidizing effects via inducing the antioxidant effects of catalase and SOD in the U87 cell line. Therefore, this drug might be introduced as a potential candidate for controlling glioblastoma cancer in animal models and clinical trials.

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“…SP plays roles in neurogenic inflammation, wound healing, pain transmission, and vasodilatation. By activating NK-1R, it can induce tumor-initiating intracellular responses in various cancers, including lung cancer [ 24 ], retinoblastoma [ 25 ], glioblastomas [ 26 ], breast cancer [ 27 ], and pancreatic cancer [ 28 ], and is correlated with cancer development and progression. The SP/NK-1R can substantially promote the activation of NF- κ B, which positively regulates transcription factors that favor tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

A Substance P (SP)/Neurokinin-1 Receptor Axis Promotes Perineural Invasion of Pancreatic Cancer and Is Affected by lncRNA LOC389641

et al. 2022

Journal of Immunology Research

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Perineural invasion (PNI) is considered to be a main reason for the poor prognosis of pancreatic cancer. In the present study, we analyzed the roles of substance P (SP)/neurokinin-1 receptor (NK-1R) and lncRNA LOC389641 in pancreatic cancer PNI. Pancreatic cancer cell lines BxPC-3 and MIAPaCa-2 were cocultured with SH-SY5Y cells and then stimulated with SP to simulate the in vivo influence of ganglia on pancreatic cancer. The BxPC-3 and MIAPaCa-2 cells were transfected with a neurokinin-1 receptor (NK-1R) overexpression vector, NK-1R silencing vector, LOC389641 overexpression vector, or LOC389641 silencing vector, respectively. The proliferative abilities of BxPC-3 and MIAPaCa-2 cells were assessed using the cell counting kit-8 and 5-ethynyl-2 ′ -deoxyuridine (EdU) assays. Wound-healing and Transwell assays were performed to determine the migration and invasion abilities of the cells. When SP was added to the coculture system, it positively regulated cancer cell proliferation, migration, and PNI and significantly activated the NK-1R/Akt/NF-κB signaling pathway. Incubation with 100 nmol/L SP for 24 h was selected as the optimal condition for treatment. The activated NK-1R positively regulated the proliferation, migration, and invasion of pancreatic cancer cells. However, the levels of lncRNA LOC389641 and tumor necrosis factor receptor SF10A (TNFRSF10A) mRNA in BxPC-3 and MIAPaCa-2 cells were not affected by SP treatment. Overexpression or silencing of LOC389641 changed the effect of SP stimulation on pancreatic cancer PNI. When taken together, these results revealed that SP/NK-1R and LOC389641 promoted the progression of pancreatic cancer PNI. Moreover, we found that pancreatic cancer PNI promoted by the SP/NK-1R axis could be blocked by the TNFRSF10A/NF-κB pathway mediated by LOC389641.

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New insight into the role of substance P/neurokinin‐1 receptor system in breast cancer progression and its crosstalk with microRNAs

Cited by 30 publications

References 82 publications

Desensitization of Capsaicin-Sensitive Afferents Accelerates Early Tumor Growth via Increased Vascular Leakage in a Murine Model of Triple Negative Breast Cancer

Desensitization of Capsaicin-Sensitive Afferents Accelerates Early Tumor Growth via Increased Vascular Leakage in a Murine Model of Triple Negative Breast Cancer

The Effect of SP/NK1R on the Expression and Activity of Catalase and Superoxide Dismutase in Glioblastoma Cancer Cells

A Substance P (SP)/Neurokinin-1 Receptor Axis Promotes Perineural Invasion of Pancreatic Cancer and Is Affected by lncRNA LOC389641

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