Ungefroren Hendrik
First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Clin Sci (Lond). 2025 Feb 4;139(3):281-6. doi: 10.1042/CS20241916.
Malignant progression of pancreatic ductal adenocarcinoma (PDAC) is driven by transforming growth factor (TGF)-β1 through extensive cross-talk with other signalling pathways. Prompted by the observation that the ubiquitous protein programmed cell death 10 (PDCD10) is more abundantly expressed in PDAC tumour tissue compared with normal pancreas and highly correlated with reduced patient survival, authors examined its function as a modulator of TGF-β signalling in PDAC. Cytotoxicity assays with PDAC-derived tumour cell lines, PaTu8902 (DPC4+/+) and PaTu8988t (DPC4-/-) engineered to homozygously lack PDCD10 showed that PDCD10 renders cells more chemoresistant to anticancer drugs. Moreover, PDCD10 promoted TGF-β1-dependent proliferation by inactivating the retinoblastoma 1 protein (pRb) via a SMAD4-dependent pathway, and TGF-β1-driven EMT by increasing ERK1/2 activation via a non-SMAD4 pathway. Phosphorylation of pRB and ERK by PDCD10 is facilitated by binding of PDCD10 to MST4. Targeting PDCD10 in PDAC patients may represent a promising new strategy to improve TGF-β targeted therapies.
胰腺导管腺癌（PDAC）的恶性进展是由转化生长因子（TGF）-β1 通过与其他信号通路的广泛相互作用驱动的。鉴于普遍存在的程序性细胞死亡 10（PDCD10）蛋白在 PDAC 肿瘤组织中比正常胰腺表达更丰富，且与患者生存率降低高度相关，作者研究了其作为 PDAC 中 TGF-β信号调节剂的功能。对经过基因工程改造而纯合缺失 PDCD10 的 PDAC 来源的肿瘤细胞系 PaTu8902（DPC4+/+）和 PaTu8988t（DPC4-/-）进行的细胞毒性试验表明，PDCD10 使细胞对抗癌药物更具化学抗性。此外，PDCD10 通过依赖 SMAD4 的途径使视网膜母细胞瘤 1 蛋白（pRb）失活，从而促进 TGF-β1 依赖性增殖，并通过非 SMAD4 途径增加 ERK1/2 激活来促进 TGF-β1 驱动的上皮-间质转化（EMT）。PDCD10 与 MST4 的结合促进了 pRB 和 ERK 的磷酸化。在 PDAC 患者中靶向 PDCD10 可能是改善 TGF-β靶向治疗的一种有前景的新策略。
