Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China.
MOE Frontiers Science Centre for Precision Oncology, University of Macau, Taipa, Macau SAR, China.
Int J Biol Sci. 2023 Jul 9;19(11):3544-3557. doi: 10.7150/ijbs.82566. eCollection 2023.
Colorectal cancer (CRC) driven by deficiency exhibits high risk of metastasis, advancement of tumor stages and chemotherapy resistance, where no effective therapy has been developed. In this study, we performed a synthetic lethal drug screening in CRC and found that PTEN-deficient CRC cells are highly vulnerable to MDM2 inhibition. MDM2 inhibitor treatment or its silencing selectively inhibited the growth of PTEN-deficient CRC in vitro and in mice models. Mechanistically, PTEN loss increased the level of active AKT and subsequently increased MDM2 phosphorylation, thereby limiting the p53 functions in CRC cells. MDM2 inhibition in turn activated p53 in CRC, particularly in CRC cells. The synthetic lethal effect of MDM2 inhibitor was largely dependent on p53, because p53 silenced cells or cells lacking p53 failed to exhibit synthetic lethality in PTEN-deficient cells. We further showed that MDM2 inhibition led to the p53-dependent reversal of Bcl2-Bax ratio, which contributed to mitochondria-mediated apoptotic cell death in PTEN-deficient CRC. This study suggests that pharmacological targeting of MDM2 could be a potential therapeutic strategy for PTEN-deficient CRC.
由 缺失驱动的结直肠癌（CRC）表现出高转移风险、肿瘤分期进展和化疗耐药性，目前尚未开发出有效的治疗方法。在这项研究中，我们在 CRC 中进行了合成致死药物筛选，发现 PTEN 缺失的 CRC 细胞对 MDM2 抑制高度敏感。MDM2 抑制剂治疗或其沉默选择性地抑制了体外和小鼠模型中 PTEN 缺失的 CRC 的生长。在机制上，PTEN 的缺失增加了 AKT 的活性水平，进而增加了 MDM2 的磷酸化，从而限制了 CRC 细胞中 p53 的功能。MDM2 抑制反过来在 CRC 中激活了 p53，特别是在 CRC 细胞中。MDM2 抑制剂的合成致死效应在很大程度上依赖于 p53，因为沉默 p53 的细胞或缺乏 p53 的细胞在 PTEN 缺失的细胞中未能表现出合成致死性。我们进一步表明，MDM2 抑制导致了 p53 依赖性 Bcl2-Bax 比值的逆转，这有助于 PTEN 缺失的 CRC 中线粒体介导的细胞凋亡死亡。这项研究表明，靶向 MDM2 的药理学方法可能是治疗 PTEN 缺失的 CRC 的一种潜在治疗策略。
