Kisspeptin inhibits cancer growth and metastasis via activation of EIF2AK2.

Kisspeptin is a protein encoded by the KISS1 gene, which has been reported to suppress the metastatic capabilities of various types of cancer cells, through the activation of its G‑protein coupled receptor GPR54. However, the molecular mechanisms underlying the involvement of kisspeptin‑mediated signaling in the inhibition of cancer cell migration and invasion have yet to be elucidated. The present in vitro cell proliferation, migration and invasion assays and in vivo experimental metastasis studies demonstrated that kisspeptin‑induced eukaryotic translation initiation factor 2α kinase 2 (EIF2AK2) activation suppressed the metastatic capabilities of several types of cancer cells. Kisspeptin was revealed to inhibit the migratory and invasive abilities of highly metastatic breast SK‑BR‑3, prostatic PC‑3 and colorectal adenocarcinoma LoVo human cancer cell lines, whereas its inhibitory effects were abolished following the silencing of EIF2AK2 expression using RNA interference. Similarly, kisspeptin failed to inhibit the migration and invasion of mouse embryonic fibroblasts following the deletion of the EIF2AK2 gene. Furthermore, kisspeptin was demonstrated to activate Ras homolog gene family member A (RhoA)‑dependent signaling, and to phosphorylate EIF2AK2 via RhoA‑mediated pathways in various cancer cells. In addition, results obtained from nude mice bearing LoVo‑derived xenograft tumors revealed that kisspeptin inhibited tumor growth through an EIF2AK2‑dependent mechanism, and an in vivo metastasis assay identified kisspeptin‑activated EIF2AK2 signaling as critical for the suppression of distant metastasis. The present study concluded that kisspeptin represses cancer metastasis via EIF2AK2 signaling, thus clarifying the role of kisspeptin signaling in complicated cancer metastasis signaling network. Therefore, kisspeptin treatment may be a choice for blocking metastases.