ABSTRACT

Prolyl endopeptidase (PREP), also known as prolyl oligopeptidase (POP), is an enzyme that cleaves short peptides (<30 amino acids in length) on the C-terminal side of proline. PREP is highly expressed in multiple carcinomas and is a potential target for cancer therapy. A potent inhibitor of PREP, Y-29794, causes long-lasting inhibition of PREP in mouse tissues. However, there are no reports on Y-29794 effects on cancer cell and tumor proliferation. Using cell line models of aggressive triple-negative breast cancer (TNBC), we show here that Y-29794 inhibited proliferation and induced death in multiple TNBC cell lines. Cell death induced by Y-29794 coincided with inhibition of the IRS1-AKT-mTORC1 survival signaling pathway, although stable depletion of PREP alone was not sufficient to reduce IRS1-AKT-mTORC1 signaling or induce death. These results suggest that Y-29794 elicits its cancer cell killing effect by targeting other mechanisms in addition to PREP. Importantly, Y-29794 inhibited tumor growth when tested in xenograft models of TNBC in mice. Induction of cell death in culture and inhibition of xenograft tumor growth support the potential utility of Y-29794 or its derivatives as a treatment option for TNBC tumors.

摘要

脯氨酰内肽酶 (PREP)，也称为脯氨酰寡肽酶 (POP)，是一种在脯氨酸 C 端切割短肽（长度<30 个氨基酸）的酶。PREP 在多种癌症中高度表达，是癌症治疗的潜在靶点。一种有效的 PREP 抑制剂 Y-29794，可对小鼠组织中的 PREP 产生长期抑制作用。然而，没有关于 Y-29794 对癌细胞和肿瘤增殖的影响的报道。使用侵袭性三阴性乳腺癌 (TNBC) 的细胞系模型，我们在这里展示了 Y-29794 在多个 TNBC 细胞系中抑制增殖并诱导死亡。Y-29794 诱导的细胞死亡与 IRS1-AKT-mTORC1 存活信号通路的抑制相吻合，尽管单独稳定消耗 PREP 不足以减少 IRS1-AKT-mTORC1 信号传导或诱导死亡。这些结果表明，Y-29794 通过靶向除 PREP 之外的其他机制来引发其癌细胞杀伤作用。重要的是，当在小鼠的 TNBC 异种移植模型中测试时，Y-29794 抑制了肿瘤生长。培养中细胞死亡的诱导和异种移植肿瘤生长的抑制支持 Y-29794 或其衍生物作为 TNBC 肿瘤治疗选择的潜在效用。