Kisspeptin-10 inhibits ovarian cancer cell proliferation and metastasis by targeting the SP1-hTERT-ZEB1 axis

Ovarian cancer remains one of the deadliest gynecological malignancies, largely due to its high metastatic potential and frequent telomerase reactivation, which fuels uncontrolled cell growth. Current standard-of-care treatments, while often achieving initial response, struggle with recurrence and drug resistance, highlighting an urgent need for novel therapeutic strategies. The SP1-ZEB1-hTERT regulatory axis is a critical oncogenic pathway implicated in both telomerase activity and epithelial-mesenchymal transition (EMT), making it an attractive target. Kisspeptin-10 (KP-10), a neuropeptide known for its role in reproductive physiology, has also shown emerging anti-cancer properties, prompting investigation into its specific mechanisms in ovarian cancer.

Researchers investigated the effects of exogenous Kisspeptin-10 (KP-10) on SKOV-3 human ovarian cancer cell lines using both in vitro assays and computational techniques. Cells were treated with varying doses of KP-10 to determine its impact on proliferation, migration, and invasion. Cell viability was assessed to establish an IC₅₀ value. Molecular mechanisms were explored by measuring the expression of key transcriptional factors (SP1, CDX2, GATA2, FLI1, ZEB1) and hTERT (human telomerase reverse transcriptase) via qPCR. Additionally, the study analyzed the influence of KP-10 on tumor suppressive microRNAs (miR-200, miR-345, miR-577) and performed bioinformatics analysis of the KISS1 promoter to identify transcription factor binding sites.

Kisspeptin-10 (KP-10) demonstrated a significant, dose-dependent inhibition of SKOV-3 ovarian cancer cell proliferation, migration, and invasion. The IC₅₀ for KP-10 in inhibiting proliferation was determined to be 72.28 nM. Molecular analysis revealed that KP-10 effectively modulated the expression of several critical transcriptional factors. Specifically, it influenced the regulation of SP1, CDX2, GATA2, FLI1, and ZEB1, alongside a notable impact on hTERT expression, indicating a direct modulation of telomerase-related oncogenic signaling. This suggests KP-10 disrupts a core pathway driving cancer progression. Furthermore, KP-10 treatment influenced the expression of key tumor suppressive microRNAs: miR-200, miR-345, and miR-577. These microRNAs are known to play vital roles in inhibiting epithelial-mesenchymal transition (EMT), cellular invasion, and overall cancer development. Bioinformatics analysis supported these findings by identifying multiple binding sites for SP1, CDX2, GATA2, and FLI1 within the KISS1 promoter, underscoring the complex transcriptional network involved in KISS1 regulation and its potential anti-cancer effects. > KP-10 significantly inhibited SKOV-3 proliferation, migration, and invasion at an IC₅₀ of 72.28 nM, directly impacting the SP1-ZEB1-hTERT pathway.