Division of Oncogenomics, Oncode Institute, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
Mol Cell. 2021 Nov 18;81(22):4709-4721.e9. doi: 10.1016/j.molcel.2021.09.002. Epub 2021 Sep 24.
mRNA translation is a highly conserved and tightly controlled mechanism for protein synthesis. Despite protein quality control mechanisms, amino acid shortage in melanoma induces aberrant proteins by ribosomal frameshifting. The extent and the underlying mechanisms related to this phenomenon are yet unknown. Here, we show that tryptophan depletion-induced ribosomal frameshifting is a widespread phenomenon in cancer. We termed this event sloppiness and strikingly observed its association with MAPK pathway hyperactivation. Sloppiness is stimulated by RAS activation in primary cells, suppressed by pharmacological inhibition of the oncogenic MAPK pathway in sloppy cells, and restored in cells with acquired resistance to MAPK pathway inhibition. Interestingly, sloppiness causes aberrant peptide presentation at the cell surface, allowing recognition and specific killing of drug-resistant cancer cells by T lymphocytes. Thus, while oncogenes empower cancer progression and aggressiveness, they also expose a vulnerability by provoking the production of aberrant peptides through sloppiness.
mRNA 翻译是一种高度保守且严格控制的蛋白质合成机制。尽管存在蛋白质质量控制机制，但黑色素瘤中的氨基酸短缺会通过核糖体移码导致异常蛋白的产生。目前尚不清楚这种现象的程度和相关的潜在机制。在这里，我们表明色氨酸耗尽诱导的核糖体移码是癌症中的一种普遍现象。我们将这种现象称为草率，并惊人地观察到它与 MAPK 途径的过度激活有关。草率性受 RAS 激活刺激，在草率细胞中被致癌 MAPK 途径的药物抑制所抑制，并在获得 MAPK 途径抑制耐药的细胞中恢复。有趣的是，草率性导致细胞表面异常肽的呈现，允许 T 淋巴细胞识别和特异性杀伤耐药癌细胞。因此，虽然癌基因赋予癌症进展和侵袭性，但它们通过草率性引起异常肽的产生也暴露了一个弱点。
