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.
自噬在乳腺癌细胞存活、转移及化疗耐药中扮演着复杂角色。二肽基肽酶（DPP）-4作为2型糖尿病的治疗靶点，同样参与自噬流调控，但其抑制对癌症生物学的潜在影响尚不明确。本研究揭示DPP-4缺陷通过C-X-C基序趋化因子12（CXCL12）/C-X-C受体4（CXCR4）/哺乳动物雷帕霉素靶蛋白（mTOR）/缺氧诱导因子（HIF）-1α轴诱导自噬，从而促进乳腺癌细胞存活。在人源乳腺癌细胞及小鼠乳腺癌细胞中，DPP-4基因敲除与DPP-4抑制剂KR62436（KR）处理均能提升LC3II与HIF-1α表达水平。CXCR4抑制剂AMD3100及雷帕霉素可抑制KR诱导的癌细胞自噬表型，而HIF-1α敲除同样能阻断KR引发的乳腺癌自噬。自噬抑制剂3-甲基腺嘌呤可显著抑制KR介导的cleaved caspase-3水平下降及乳腺癌细胞凋亡。最后研究发现，二甲双胍诱导的DPP-4缺陷型4T1乳腺癌细胞凋亡与自噬抑制相关。本研究表明DPP-4抑制可通过激活CXCL12/CXCR4/mTOR/HIF-1α轴依赖性自噬促进乳腺癌存活，而二甲双胍是潜在逆转该存活机制的有效药物。
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