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

Emi Kawakita; Fan Yang; Sen Shi; Yuta Takagaki; Daisuke Koya; Keizo Kanasaki

doi:10.3390/cancers15184529

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

Cancers (Basel). 2023 Sep 12;15(18):4529. doi: 10.3390/cancers15184529.

Authors

Emi Kawakita^{1

2}, Fan Yang^{2

3}, Sen Shi^{2

4}, Yuta Takagaki², Daisuke Koya^{2

5}, Keizo Kanasaki^{1

2

5}

Affiliations

¹ Department of Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan.
² Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan.
³ Department of Emergency Medicine, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
⁴ Division of Vascular Surgery, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
⁵ Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan.

Abstract

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.

Keywords: DPP-4; HIF-1α; apoptosis; autophagy; breast cancer; metformin.

Grants and funding

F.Y. is supported by the Japanese Government MEXT (Ministry of Education, Culture, Sports, Science, and Technology) Fellowship Program (142309). This study was partially supported by grants from the Japan Society for the Promotion of Science awarded to K.K. (23790381, 26460403), DK (25282028, 25670414), and Y.T. (18K16214). This study was supported by a Grant for JSPS KAKENHI awarded to E.K. (23K14567). This study was partially supported by a Grant for Collaborative Research awarded to D.K. (C2011-4, C2012-1), a Grant for Promoted Research awarded to K.K. (S2016-3, S2017-1), and a Grant for Assist KAKEN awarded to Y.T. (K2017-16) from Kanazawa Medical University. This study was also partially supported by the Lilly Incretin Basic Research Grant from the Japan Diabetes Foundation awarded to Y.T.