Investigating the potential role of α-SNAP in preventing chemotherapy-induced ovarian dysfunction: Insights from cellular and animal models.

BACKGROUND

The phosphoinositide 3-kinase/Akt/mammalian target of rapamycin complex 1 (PI3K/Akt/mTORC1) pathway plays a crucial role in the activation of primordial follicles. However, excessive activation and the loss of primordial follicles can lead to ovarian dysfunction. The alpha-soluble N-ethylmaleimide sensitive factor attachment protein (α-SNAP) protein has been implicated in PI3K/Akt/mTORCl signaling, suggesting its potential involvement in follicle activation. Thus, this study aimed to explore the role of α-SNAP in the activation of the PI3K/Akt/mTORC1 signaling pathway and its ability to mitigate the effects of cisplatin on ovarian function, using both in vitro and in vivo models.

METHODS

We transfected KGN human ovarian granulosa cells (GCs) with small interfering RNA (siRNA) targeting α-SNAP to investigate the effects of α-SNAP inhibition on GC proliferation and apoptosis, as well as on the activity of the PI3K/Akt/mTORC1 pathway. In a mouse model, α-SNAP siRNA was delivered via an adeno-associated virus before treatment with cisplatin to assess its effects on follicle activation and ovarian function. Follicle counts at various growth stages, western blotting, and immunohistochemistry analyses were conducted to detect the expression of cleaved caspase-3, Ki67, α-SNAP, and p-mTOR. Additionally, the serum concentrations of anti-Müllerian hormone (AMH) were measured through an enzyme-linked immunosorbent assay.

RESULTS

In vitro, α-SNAP depletion prevented GC proliferation by inhibiting the PI3K/Akt/mTORC1 pathway, thereby indicating its role in the regulation of cell growth. In vivo, α-SNAP knockdown attenuated the cisplatin-induced overactivation of primordial follicles by suppressing the PI3K/Akt/mTORC1 signaling pathway and partially restoring AMH levels. In addition, the expression and distribution patterns of cleaved caspase-3, Ki67, α-SNAP, and p-mTOR varied across different follicular growth stages, suggesting a protective effect against chemotherapy-induced ovarian damage.

CONCLUSIONS

Inhibiting α-SNAP may attenuate GC proliferation by suppressing the PI3K/Akt/mTORC1 pathway, thereby mitigating the overactivation and loss of primordial follicles induced by cisplatin. Targeting α-SNAP may emerge as a novel strategy to prevent ovarian damage resulting from chemotherapy. However, these conclusions warrant repeated testing, and the mechanistic underpinnings of α-SNAP must be further elucidated in the future.