HIF-1α Inhibition Sensitized Pituitary Adenoma Cells to Temozolomide by Regulating Presenilin I Expression and Autophagy

Pituitary adenomas usually develop temozolomide resistance, which could compromise the anticancer effects of temozolomide. Suppression of hypoxia-inducible factor 1 alpha has been shown to sensitize glioblastoma cells to temozolomide treatment according to previous reports. However, whether and how the suppression of hypoxia-inducible factor 1 alpha could sensitize pituitary adenomas to temozolomide treatment are still poorly understood. In the present study, using hypoxia-inducible factor 1 alpha knockdown strategy, we demonstrated for the first time that hypoxia-inducible factor 1 alpha knockdown could inhibit temozolomide-induced autophagy in rat pituitary adenoma GH3 cells and thus increase antitumor efficacy of temozolomide. Furthermore, we found hypoxia-inducible factor 1 alpha knockdown could block autophagy process through neutralizing lysosomal pH value but not inhibiting autophagy induction. Finally, we found hypoxia-inducible factor 1 alpha could regulate lysosomal pH value through regulating full length presenilin I expression, and exogenous reexpression of presenilin I could restore lysosome acidic levels. Our data indicated hypoxia-inducible factor 1 alpha knockdown could be a potential approach to improve the efficacy of temozolomide therapy for pituitary adenomas.