The Neurokinin-1 Receptor Is a Target in Pediatric Rhabdoid Tumors

Abstract

Rhabdoid tumors (RT) are among the most aggressive tumors in early childhood. Overall survival remains poor, and treatment only effectively occurs at the cost of high toxicity and late adverse effects. It has been reported that the neurokinin-1 receptor/ substance P complex plays an important role in cancer and proved to be a promising target. However, its role in RT has not yet been described. This study aims to determine whether the neurokinin-1 receptor is expressed in RT and whether neurokinin-1 receptor (NK1R) antagonists can serve as a novel therapeutic approach in treating RTs. By in silico analysis using the cBio Cancer Genomics Portal we found that RTs highly express neurokinin-1 receptor. We confirmed these results by RT-PCR in both tumor cell lines and in human tissue samples of various affected organs. We demonstrated a growth inhibitory and apoptotic effect of aprepitant in viability assays and flow cytometry. Furthermore, this effect proved to remain when used in combination with the cytostatic cisplatin. Western blot analysis showed an upregulation of apoptotic signaling pathways in rhabdoid tumors when treated with aprepitant. Overall, our findings suggest that NK1R may be a promising target for the treatment of RT in combination with other anti-cancer therapies and can be targeted with the NK1R antagonist aprepitant.

Aprepitant inhibits the development and metastasis of gallbladder cancer via ROS and MAPK activation

“…Earlier research described that the anticancer effect of aprepitant depends partly on inducing apoptosis, which seems to be a common mechanism of aprepitant-induced cell death in diverse tumor backgrounds [23,24,41]. Apoptosis is a programmed death process initiated by endogenous or exogenous signals, and causing apoptosis can effectively inhibit the occurrence and development of tumors.…”

Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer

“…New, promising molecular targets to block tumor development and new compounds capable of specifically destroying cancer cells must be urgently investigated. In recent years, the knowledge on the involvement of the substance P (SP)/neurokinin-1 receptor (NK-1R) system in cancer has attracted increasing interest [ 1 , 2 , 3 , 4 , 5 ]. This has opened up new research lines and possibilities to improve cancer diagnosis and to explore new therapeutic strategies targeting tumor-specific molecular derangements since SP/NK-1R expression has been associated with cancer development and poor prognosis [ 1 , 2 , 3 , 4 , 5 ].…”

“…In recent years, the knowledge on the involvement of the substance P (SP)/neurokinin-1 receptor (NK-1R) system in cancer has attracted increasing interest [ 1 , 2 , 3 , 4 , 5 ]. This has opened up new research lines and possibilities to improve cancer diagnosis and to explore new therapeutic strategies targeting tumor-specific molecular derangements since SP/NK-1R expression has been associated with cancer development and poor prognosis [ 1 , 2 , 3 , 4 , 5 ]. SP, an undecapeptide that binds preferentially to NK-1R, plays crucial roles in cancer development [ 1 , 2 , 3 , 4 , 5 , 6 ]: (1) it promotes the mitogenesis/migration of tumor cells; (2) it exerts antiapoptotic action; (3) it increases the glycolytic rate (Warburg effect); (4) it stimulates the growth of blood vessels, and (5) tumor cells also synthesize and release SP, which acts through autocrine, paracrine, and neuroendocrine (tumor mass) mechanisms.…”

“…This has opened up new research lines and possibilities to improve cancer diagnosis and to explore new therapeutic strategies targeting tumor-specific molecular derangements since SP/NK-1R expression has been associated with cancer development and poor prognosis [ 1 , 2 , 3 , 4 , 5 ]. SP, an undecapeptide that binds preferentially to NK-1R, plays crucial roles in cancer development [ 1 , 2 , 3 , 4 , 5 , 6 ]: (1) it promotes the mitogenesis/migration of tumor cells; (2) it exerts antiapoptotic action; (3) it increases the glycolytic rate (Warburg effect); (4) it stimulates the growth of blood vessels, and (5) tumor cells also synthesize and release SP, which acts through autocrine, paracrine, and neuroendocrine (tumor mass) mechanisms. Moreover, tumor cells also overexpress NK-1R, which is involved in their viability; however, it has recently been demonstrated that this receptor is not essential for the viability of normal cells [ 7 ].…”

“…What if it was simply a question of dosage [ 17 ]? The knowledge on the involvement of SP/NK-1R in cancer has increased in recent years thanks to a few researchers and laboratories around the world [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 17 , 18 , 19 , 20 , 21 , 22 ]; the findings reported by these researchers greatly support the initiation of clinical studies to confirm the antitumor action of aprepitant. We hope that this Special Issue will serve to increase the scientific interest for the SP/NK-1R system, not only among basic researchers but also in the pharmaceutical industry, to join forces to fight cancer.…”