Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.
Department of Oncology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, P.R. China.
Cancer Res. 2021 Jun 15;81(12):3215-3228. doi: 10.1158/0008-5472.CAN-20-3738. Epub 2021 Apr 5.
As a cytoplasmic sensor of double-stranded DNA (dsDNA), the cyclic GMP-AMP synthase-stimulator of IFN genes (STING) pathway plays an important role in antitumor immunity. In this study, we investigated the effect of Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) on tumor cell-intrinsic STING pathway activity and DNA repair in colon cancer. SHP2 interacted with and dephosphorylated PARP1 after DNA damage. PARP1 inhibition by SHP2 resulted in reduced DNA repair and accumulation of dsDNA in cells, thus promoting hyperactivation of the STING pathway. The SHP2 agonist lovastatin was able to enhance SHP2 activity and promote STING pathway activation. Moreover, lovastatin significantly enhanced the efficacy of chemotherapy in colon cancer models, in part via STING pathway-mediated antitumor immunity. These findings suggest that SHP2 exacerbates STING pathway activation by restricting PARP1-mediated DNA repair in tumor cells, providing a basis for the combined use of lovastatin and chemotherapy in the treatment of colon cancer. SIGNIFICANCE: Dephosphorylation of PARP1 by SHP2 simultaneously suppresses DNA repair and enhances STING pathway-mediated antitumor immunity, highlighting SHP2 activation as a potential therapeutic approach in colon cancer.
作为双链 DNA（dsDNA）的细胞质传感器，环鸟苷酸-腺苷酸合酶刺激干扰素基因（STING）途径在抗肿瘤免疫中发挥着重要作用。在这项研究中，我们研究了 Src 同源-2 结构域蛋白酪氨酸磷酸酶-2（SHP2）对结肠癌中肿瘤细胞内在的 STING 途径活性和 DNA 修复的影响。SHP2 在 DNA 损伤后与 PARP1 相互作用并使其去磷酸化。SHP2 对 PARP1 的抑制导致 DNA 修复减少和细胞内 dsDNA 积累，从而促进 STING 途径的过度激活。SHP2 激动剂洛伐他汀能够增强 SHP2 的活性并促进 STING 途径的激活。此外，洛伐他汀通过 STING 途径介导的抗肿瘤免疫显著增强了结肠癌模型中的化疗效果，部分原因是通过 SHP2 途径介导的抗肿瘤免疫。这些发现表明，SHP2 通过限制 PARP1 介导的肿瘤细胞内 DNA 修复来加剧 STING 途径的激活，为洛伐他汀与化疗联合治疗结肠癌提供了依据。意义：SHP2 通过磷酸化 PARP1 同时抑制 DNA 修复并增强 STING 途径介导的抗肿瘤免疫，突出了 SHP2 激活作为结肠癌潜在的治疗方法。
