Inhibition of Dipeptidyl Peptidase-4 Activates Autophagy to Promote Survival of Breast Cancer Cells via the mTOR/HIF-1α Pathway.

Autor: Kawakita E; Department of Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan.; Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan., Yang F; Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan.; Department of Emergency Medicine, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China., Shi S; Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan.; Division of Vascular Surgery, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China., Takagaki Y; Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan., Koya D; Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan.; Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan., Kanasaki K; Department of Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan.; Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan.; Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2023 Sep 12; Vol. 15 (18). Date of Electronic Publication: 2023 Sep 12.
DOI: 10.3390/cancers15184529
Abstrakt: Autophagy plays a complex role in breast cancer cell survival, metastasis, and chemotherapeutic resistance. Dipeptidyl peptidase (DPP)-4, a therapeutic target for type 2 diabetes mellitus, is also involved in autophagic flux. The potential influence of DPP-4 suppression on cancer biology remains unknown. Here, we report that DPP-4 deficiency promotes breast cancer cell survival via the induction of autophagy by the C-X-C motif chemokine 12 (CXCL12)/C-X-C receptor 4 (CXCR4)/mammalian target of rapamycin (mTOR)/hypoxia inducible factor (HIF)-1α axis. DPP-4 knockdown and DPP-4 inhibitor KR62436 (KR) treatment both increased the levels of LC3II and HIF-1α in cultured human breast and mouse mammary cancer cells. The KR-induced autophagic phenotype in cancer cells was inhibited by treatment with the CXCR4 inhibitor AMD3100 and rapamycin. HIF-1α knockdown also suppressed breast cancer autophagy induced by KR. The autophagy inhibitor 3-methyladenine significantly blocked the KR-mediated suppression of cleaved caspase-3 levels and apoptosis in breast cancer cell lines. Finally, we found that the metformin-induced apoptosis of DPP-4-deficient 4T1 mammary cancer cells was associated with the suppression of autophagy. Our findings identify a novel role for DPP-4 inhibition in the promotion of breast cancer survival by inducing CXCL12/CXCR4/mTOR/HIF-1α axis-dependent autophagy. Metformin is a potential drug that counteracts the breast cancer cell survival system.
Databáze: MEDLINE
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