Neuropeptide Substance P Enhances Inflammation-Mediated Tumor Signaling Pathways and Migration and Proliferation of Head and Neck Cancers

Singh, Sumeet Pal; Kumaravel, Subhashree; Dhole, Saurabh; Roy, Sukanya; Pavan, Vani; Chakraborty, Sanjukta

doi:10.1007/s13193-020-01210-7

Cited by 15 publications

(10 citation statements)

References 35 publications

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“…A picture of the wound was taken at 0 h, 4 h, 6 h, 12 h, 24 h and 48 h. Migration rate was expressed as the average migration rate in µm/h. Wound length was measured by ImageJ [25].…”

Section: Scratch Wound Assaymentioning

confidence: 99%

Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma

Roy

Kumaravel

Banerjee

et al. 2021

Cells

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Cholangiocarcinoma (CCA), or cancer of bile duct epithelial cells, is a very aggressive malignancy characterized by early lymphangiogenesis in the tumor microenvironment (TME) and lymph node (LN) metastasis which correlate with adverse patient outcome. However, the specific roles of lymphatic endothelial cells (LECs) that promote LN metastasis remains unexplored. Here we aimed to identify the dynamic molecular crosstalk between LECs and CCA cells that activate tumor-promoting pathways and enhances lymphangiogenic mechanisms. Our studies show that inflamed LECs produced high levels of chemokine CXCL5 that signals through its receptor CXCR2 on CCA cells. The CXCR2-CXCL5 signaling axis in turn activates EMT (epithelial-mesenchymal transition) inducing MMP (matrix metalloproteinase) genes such as GLI, PTCHD, and MMP2 in CCA cells that promote CCA migration and invasion. Further, rate of mitochondrial respiration and glycolysis of CCA cells was significantly upregulated by inflamed LECs and CXCL5 activation, indicating metabolic reprogramming. CXCL5 also induced lactate production, glucose uptake, and mitoROS. CXCL5 also induced LEC tube formation and increased metabolic gene expression in LECs. In vivo studies using CCA orthotopic models confirmed several of these mechanisms. Our data points to a key finding that LECs upregulate critical tumor-promoting pathways in CCA via CXCR2-CXCL5 axis, which further augments CCA metastasis.

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“…A picture of the wound was taken at 0 h, 4 h, 6 h, 12 h, 24 h and 48 h. Migration rate was expressed as the average migration rate in µm/h. Wound length was measured by ImageJ [25].…”

Section: Scratch Wound Assaymentioning

confidence: 99%

Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma

Roy

Kumaravel

Banerjee

et al. 2021

Cells

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“…NK-1R antagonists have been also reported to inhibit the metastasis-promoting genes, including MMPs, and EMT-inducing genes in head and neck cancers [ 34 ]. NK-1R antagonist, L703606, could also attenuate the expression of metastasis-related factors like MMP9 in gallbladder cancer cells [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

The Potential In Vitro Inhibitory Effects of Neurokinin‐1 Receptor (NK‐1R) Antagonist, Aprepitant, in Osteosarcoma Cell Migration and Metastasis

Alsaeed

Ebrahimi

Alalikhan

et al. 2022

BioMed Research International

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Background. Osteosarcoma, the most frequent osteogenic malignancy, has become a serious public health challenge due to its high morbidity rates and metastatic potential. Recently, the neurokinin-1 receptor (NK-1R) is proved to be a promising target in cancer therapy. This study is aimed at determining the effect of aprepitant, a safe and Food and Drug Administration (FDA) approved NK-1R antagonist, on osteosarcoma cell migration and metastasis, and to explore its underlying mechanism of action. Methods. Colorimetric MTT assay was employed to assess cell viability and cytotoxicity. A wound-healing assay was used to examine migration ability. The desired genes’ protein and mRNA expression levels were measured by western blot assay and quantitative real-time PCR (qRT-PCR), respectively. Gelatinase activity was also measured by zymography. Results. We found that aprepitant inhibited MG-63 osteosarcoma cell viability in a dose-dependent manner. We also observed that aprepitant inhibited the migrative phenotype of osteosarcoma cells and reduced the expression levels and activities of matrix metalloproteinases (MMP-2 and MMP-9). Aprepitant also reduced the expression of an angiogenic factor, VEGF protein, and NF-κB as an important transcriptional regulator of metastasis-related genes. Conclusion. Collectively, our observations indicate that aprepitant modulates the metastatic behavior of human osteosarcoma cells, which may be applied to an effective therapeutic approach for patients with metastatic osteosarcoma.

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“…[163][164][165] SP further activates inflammatory pathways in macrophages and fibroblasts via ERK/p38 MAPK-mediated NF-kB activation, further enhancing EMT and MMP release, a process critical for cancer invasion and metastasis. [166] Additionally, SP triggers MMP-2 and MMP-14 overexpression via activation of ERK1/2, JNK, and Akt pathways, leading to cell proliferation and ECM invasion in breast cancer cells. [167,168] 3) The PI3K/AKT signaling pathway plays a crucial role in cell proliferation and apoptosis resistance by interacting with the p53 tumor-suppressor pathway in malignant cells.…”

Section: Neuropeptide Ymentioning

confidence: 99%

Neuropeptides in Cancer: Friend and Foe?

Berisha

Borniger

2022

Advanced Biology

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highly dynamic network of various cell types (e.g., cancer cells, endothelial cells, immune cells, fibroblasts) that exert differential effects on neuronal activity within the local environment. Thus, complex signaling between cancer and stromal cells in the TME results in altered firing rates of local nerves. Reciprocally, increased neuronal activity and subsequent release of classical neurotransmitters and/or neuropeptides within the TME results in enhanced cancer progression and subsequent metastasis in various preclinical models and clinical studies. [5][6][7][8][9] Nerves interact with multiple stromal cells in the TME where they indirectly promote tumor growth, progression, and subsequent metastasis. [10] Several studies have demonstrated that sympathetic nerve innervation and subsequent release of the neurotransmitter norepinephrine (NE) is increased in breast tumors. [6,8,9] However, recent work has demonstrated that there is an inverse relationship between tumor weight and norepinephrine content (i.e., larger the size of the tumor, the lower the levels of NE), despite increased innervation of sympathetic nerves within the TME. [11] These findings may be attributed to a relatively unexplored phenomenon: neuropeptide release within the TME. Neuropeptides are molecular messengers that regulate a variety of functions in the central and peripheral nervous systems via binding G-protein-coupled receptors (GPCRs) on target cells. One of the many functions of neuropeptides is serving as growth factors for normal cells via the activation of the heterotrimeric G protein Gq and subsequent synthesis of second messengers and engagement of tyrosine phosphorylation cascades. Neuropeptides act as neuromodulators, in that they can alter the response of neurons to neurotransmitters and other circulating signals, such as leptin, ghrelin, glucose, and insulin-all of which are affected during cancer progression. [12][13][14][15][16][17] For example, both neuropeptide Y (NPY) and hypocretin/orexin neurons appear to mediate some of the orexigenic effects of centrally administered ghrelin as administration of NPY receptor antagonists attenuated ghrelininduced feeding. Similarly, ghrelin-induced feeding was suppressed in orexin knockout mice, indicating that ghrelin may stimulate feeding through both the orexin and NPY systems. [18] However, neuropeptide signaling is exploited within cancer cells and many studies demonstrate the contribution of neuropeptides in tumor cell proliferation and migration, [19] with many major neuropeptides also potentially contributing to cancer processes (see Table 1). Additionally, neuropeptides exert direct Neuropeptides are small regulatory molecules found throughout the body, most notably in the nervous, cardiovascular, and gastrointestinal systems. They serve as neurotransmitters or hormones in the regulation of diverse physiological processes. Cancer cells escape normal growth control mechanisms by altering their expression of growth factors, receptors, or intracellular signals, and neuropeptid...

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Neuropeptide Substance P Enhances Inflammation-Mediated Tumor Signaling Pathways and Migration and Proliferation of Head and Neck Cancers

Cited by 15 publications

References 35 publications

Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma

Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma

The Potential In Vitro Inhibitory Effects of Neurokinin‐1 Receptor (NK‐1R) Antagonist, Aprepitant, in Osteosarcoma Cell Migration and Metastasis

Neuropeptides in Cancer: Friend and Foe?

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