Targeting of substance P induces cancer cell death and decreases the steady state of EGFR and Her2

Abstract

NK1 is a tachykinin receptor highly relevant to tumorigenesis and metastasis development in breast cancer and other carcinomas. Despite the substantial efforts done to develop potent NK1 receptor antagonists, none of these antagonists had shown good antitumor activity in clinical trials. Now, we have tested the effect of inhibition of the neuropeptide Substance P (SP), a NK1 ligand, as a potential therapeutic approach in cancer. We found that the inhibition of SP with antibodies strongly inhibit cell growth and induce apoptosis in breast, colon, and prostate cancer cell lines. These effects were accompained by a decrease in the mitogen-activated kinase singaling pathway. Interestingly, in some cell lines SP abrogation decreased the steady state of Her2 and EGFR, suggesting that SP-mediated signaling is important for the basal activity of these ErbB receptors. In consequence, we observed a blockade of the cell cycle progression and the inhibition of several cell cycle-related proteins including mTOR. SP inhibition also induced cell death in cell lines resistant to Lapatinib and Trastuzumab that have increased levels of active Her2, suggesting that this therapeutic approach could be also effective for those cancers resistant to current anti-ErbB therapies. Thus, we propose a new therapeutic strategy for those cancers that express NK1 receptor and/or other tachykinin receptors, based in the immuno-blockade of the neuropeptide SP.

Targeting the Neurokinin-1 Receptor Compromises Canonical Wnt Signaling in Hepatoblastoma

“…This inhibition of both p70S6K and 4E-BP1/2 produced by manipulation at the NK1R is in accordance with Mayordomo and colleagues (20). However, their group treated breast, prostate, and colon cancer cells and used SP antibodies, thereby targeting NK1R's natural substrate, not the receptor itself.…”

“…The inhibitory effect of aprepitant in other cancer cells such as breast cancer cells was shown to be transmitted at least partially through ERK1/2 (20,21). However, Western blot analysis for ERK1/2 remained virtually unchanged and did not reveal uniform changes, respectively, at the protein level in the three HB cell lines investigated (Fig.…”

Therapeutic Innovations for Targeting Hepatoblastoma

“…In particular, previous work showed that the inhibition of hepatoblastoma cell growth could be achieved with the use of rapamycin through inhibition of the PI3K/AKT/mTOR pathway by dephosphorylating and deactivating p70S6K (109). Furthermore, the inhibition of both p70S6K and 4EBP1, in our study, is in accordance with Mayordomo et al (103). This group treated breast, prostate and colon cancer cells with SP antibodies, which led to the inhibition of mTOR.…”

“…The fact that cancer cells produce SP also suggests the presence of an autocrine growth stimulus pattern. Mayordomo et al used a monoclonal, specific antibody against this agonist in isolated cultures of breast cancer and other cancer cell lines and observed an inhibition of cell growth and an increase of apoptosis (103). Similarly, when using anti-SP or anti-NK1R antibodies, a significant growth inhibition was noted in our study.…”

Truncated neurokinin-1 receptor is an ubiquitous antitumor target in hepatoblastoma, and its expression is independent of tumor biology and stage

“…Aprepitant, a non-peptide NK1R antagonist, is a clinical agent approved by the Food and Drug Administration for the treatment of chemotherapy-induced nausea and vomiting. Its effects as an anticancer agent have been described extensively in vitro and in vivo (6)(7)(8)(9)(10)(11). Notably, evidence indicates that it has limited toxic side effects even when administered in high doses (6,12).…”