Hsp90α as a Promising Therapeutic Target for Suppressing Tumor Progression in Lactotroph PitNETs.

BACKGROUND Aggressive Lactotroph Pituitary Neuroendocrine Tumors(Lactotroph PitNETs) usually exhibit invasive growth behavior and resistance to dopamine agonists,showing difficulty in radical treatment and a high recurrence rate.Heat shock protein 90α(Hsp90α),a pivotal isoform of the heat shock protein 90(Hsp90) family,acts as a central chaperone that stabilizes numerous oncoproteins driving tumor progression,but its role in Lactotroph PitNETs remains unclear.

OBJECTIVE To study the effect of Hsp90α knockdown on the proliferation and invasiveness of Lactotroph PitNETs cells(MMQ).

METHODS Hsp90α and EGFR expression was compared between 18 aggressive and 22 Non-Aggressive human Lactotroph PitNETs by IHC and immunofluorescence.MMQ rat lactosomatotroph cells were transduced with lentiviral shRNA targeting Hsp90α(shHsp90α).Cell proliferation(CCK8),apoptosis(Annexin-V/7-AAD flow cytometry), Prolactin(PRL) secretion(ELISA),migration and invasion(Transwell) were assessed.Western blotting evaluated EGFR,PRL,AKT,ERK1/2,mTOR,p-AKT,p-ERK1/2 and p-mTOR.

RESULTS Aggressive Lactotroph PitNETs displayed higher Hsp90α and EGFR expression and showed a notable degree of spatial overlap.Hsp90α knockdown reduced EGFR,AKT,ERK1/2,mTOR,p-AKT,p-ERK1/2 and p-mTOR levels,decreased proliferation,increased apoptosis,lowered PRL secretion,and impaired migration and invasion.

CONCLUSIONS Hsp90α knockdown simultaneously destabilizes EGFR and its downstream AKT/mTOR and ERK axes,resulting in multi-modal suppression of Lactotroph PitNETs invasion.Targeting Hsp90α may offer a novel therapeutic strategy for Aggressive Lactotroph PitNETs refractory to standard medical therapy.