Capsaicin-induced inactivation of sensory neurons promotes a more aggressive gene expression phenotype in breast cancer cells

Erin, Nuray; Zhao, Wei; Bylander, John E.; Chase, Gary A.; Clawson, Gary A.

doi:10.1007/s10549-006-9219-7

Cited by 90 publications

(67 citation statements)

References 89 publications

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“…Epidemiologic studies suggested a positive association between the incidence of stomach cancer and the consumption of chili pepper-rich diets (7). Capsaicin enhanced the metastasis of murine breast cancer cells by reducing the expression of apoptosis-related genes (8) and induced LNCaP prostate cancer cell proliferation by increasing androgen receptor expression through the activation of ERKs and Akt (9). Thus, clarifying the underlying molecular mechanisms to reveal whether or not capsaicin exerts carcinogenic activities is important.…”

Section: Introductionmentioning

confidence: 99%

Cocarcinogenic Effect of Capsaicin Involves Activation of EGFR Signaling but Not TRPV1

et al. 2010

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Epidemiologic and animal studies revealed that capsaicin can act as a carcinogen or cocarcinogen. However, the molecular mechanisms of the cancer-promoting effects of capsaicin are not clear. Here, we report that capsaicin has a cocarcinogenic effect on 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin carcinogenesis in vivo and is mediated through the epidermal growth factor receptor (EGFR), but not the transient receptor potential vanilloid subfamily member 1 (TRPV1). Topical application of capsaicin on the dorsal skin of 7,12-dimetylbenz(a)anthracene-initiated and TPA-promoted TRPV1 wild-type (WT) and TRPV1 knockout (KO) mice induced more and larger skin tumors in TRPV1/KO mice, suggesting a TRPV1-independent mechanism. Cyclooxygenase-2 (COX-2) was highly elevated by capsaicin treatment in tumors and murine embryonic fibroblasts from TRPV1/KO mice. Inhibitors of EGFR/MEK signaling suppressed TPA/capsaicininduced COX-2 expression in TRPV1/KO cells, indicating that activation of EGFR and its downstream signaling is involved in COX-2 elevation. Capsaicin induced a further induction of TPA-increased COX-2 expression in EGFR/WT cells, but not in EGFR/KO cells. TPA/capsaicin cotreatment caused EGFR tyrosine phosphorylation and activated EGFR downstream signaling, including ERKs and Akt in EGFR/WT, but not EGFR/KO cells. Specific inhibition of EGFR and TRPV1 indicated that capsaicin-induced ERK activation in A431 cells was dependent on EGFR, but not TRPV1. Together, these findings suggest that capsaicin might act as a cocarcinogen in TPAinduced skin carcinogenesis through EGFR-dependent mechanisms. Cancer Res; 70(17); 6859-69. ©2010 AACR.

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Section: Introductionmentioning

confidence: 99%

Cocarcinogenic Effect of Capsaicin Involves Activation of EGFR Signaling but Not TRPV1

et al. 2010

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“…Hence part of VIP and majority of CGRP in our samples might be originated from infiltrating immune cells. It was previously shown that loss of peptidergic sensory neurons sensitive to capsaicin increases metastasis of breast carcinoma inducing aggressive phenotype and possibly stemness and resistance to treatment [18,20,27]. Although it was not possible to measure peptide levels in normal kidney tissues (not involved with a tumor), comparing kidney samples of different subtypes demonstrated the loss of peptidergic innervation was most obvious in kidney neighboring papillary RCC.…”

Section: Discussionmentioning

confidence: 99%

“…SP is found in both neuronal and extraneuronal cells [16] and we recently demosntrated that SP through neuroimmune modulation decreases breast cancer metastasis and enhances the therapeutic effects of radiotherapy [17]. Recent findings suggest that hydrolysis of SP by NEP produces bioactive fragments which inhibit tumor cell growth [18]. These neuropeptides, particularly CGRP and SP, are also found in capsaicin-sensitive sensory nerve fibers which may act to inhibit cancer metastasis as demonstrated in animal models [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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Neuropeptide Levels as well as Neprilysin Activity Decrease in Renal Cell Carcinoma

Erin

Ipekci

Akkaya

et al. 2016

Cancer Microenvironment

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Calcitonin Gene-related Peptide (CGRP), Vasoactive Intestinal Peptide (VIP) and Substance P (SP) are sensory neuropeptides which may alter cancer growth through modulation of chronic inflammation. We recently reported that SP suppresses breast cancer growth and metastasis through neuroimmune modulation. These neuropeptides are hydrolyzed by Neprilysin (NEP) to bioactive fragments. Decreased activity of NEP was reported in clear cell and chromophobe type renal cell carcinoma (RCC). It is however not known how the levels of neuropeptides hydrolyzed with NEP changes in RCC. Decrease activity of SP and CGRP containing sensory nerve endings was previously reported to increase cancer metastasis in animal models. It is however not known how peptidergic nerve endings are altered in RCC. Hence we here evaluated the levels of neuronal and non-neuronal neuropeptides and NEP activity in RCC including papillary type as well as neighboring uninvolved kidney. A cross-sectional study was conducted in 57 patients undergoing radical nephrectomy and diagnosed with RCC. NEP activity, levels and expression were determined using flourogenic substrate, western blot and qPCR respectively in freshly-frozen tissues. Immunohistochemical analyses were also performed.Neuronal and non-neuronal levels of CGRP, SP and VIP levels were determined using two-step acetic acid extraction. Levels and activity of NEP were markedly decreased in RCC regardless of subtype. Similar levels of VIP were detected in first and second extractions. VIP levels were higher in clear cell and papillary RCC compared to nearby kidney tissue. VIP levels of neighboring kidney tissue of papillary type RCC was significantly lower compared to kidney samples from clear cell RCC. CGRP levels were higher in second extraction. Similar to VIP levels, CGRP levels of neighboring kidney tissue from clear cell and chromophobe type RCC was significantly lower compared to corresponding tumor samples, an effect observed in the second extraction. VIP and CGRP levels of nearby kidney tissue varied subtype dependently demonstrating that different subtypes of RCC alter their local environment differently. Furthermore NEP-induce hydrolysis of VIP creates selective VPAC-1 receptor agonist which has anti-proliferative and anti-inflammatory effects. Hence loss of NEP activity may prevent antitumoral effects of VIP on RCC.

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“…These findings suggest that the autocrine secretion of SP promotes the growth and metastases of melanoma. Conversely, we observed that the depletion of SP from sensory nerve endings increased breast cancer metastases (4,5). Furthermore, treatment with SP decreased the growth of melanomas, small-cell lung cancer, colon cancer and prostate cancer (6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Radiotherapy-induced decreases in substance P levels may potentiate melanoma growth

Erin¹

2009

Mol Med Rep

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Abstract. Substance P, a member of the tachykinin family, is expressed in primary invasive malignant melanomas, metastatic melanomas, melanomas in situ, atypical naevi, and spindle and epithelioid cell naevi. The role of substance P in cancer development and progression is not clear. Radiotherapy, which is used extensively in the treatment of malignancies, alters substance P levels. It is, however, not known whether radiotherapy affects substance P levels in melanomas or in the tumor microenvironment. Given the fact that melanomas express substance P, possible radiation-induced changes in substance P content may underlie their radio-resistance. Hence, the aim of the present study was to determine the effects of radiotherapy on the growth of B16F10 melanomas as well as on the tumor and systemic expression of substance P. In vivo exposure of tumor-bearing C5BL/6 mice to ionizing radiation (45 Gy administered in three fractions) arrested tumor growth for three weeks and induced 3-fold increases in survival, as well as decreasing substance P levels in primary tumors and the surrounding skin. Although radiotherapy was applied locally (1 x 1 cm) at the mid-flank region of the animal, it also induced systemic changes in the levels of substance P. Specifically, radiotherapy decreased substance P levels in skin distant from the radiation field as well as in the lungs and adrenals. In order to understand the significance of this effect, B16F10 cells and cells made from metastatic lesions (B16LNAD cells) were treated with substance P. Substance P inhibited the growth of B16F10 and B16LNAD cells and further potentiated the inhibitory effects of radiotherapy. These findings demonstrate for the first time that substance P inhibits melanoma growth, and that radiotherapy-induced decreases in substance P levels may underlie the radio-resistance of melanomas.

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Capsaicin-induced inactivation of sensory neurons promotes a more aggressive gene expression phenotype in breast cancer cells

Cited by 90 publications

References 89 publications

Cocarcinogenic Effect of Capsaicin Involves Activation of EGFR Signaling but Not TRPV1

Cocarcinogenic Effect of Capsaicin Involves Activation of EGFR Signaling but Not TRPV1

Neuropeptide Levels as well as Neprilysin Activity Decrease in Renal Cell Carcinoma

Radiotherapy-induced decreases in substance P levels may potentiate melanoma growth

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