National Institute of Child Health and Human Development, NIH, Bethesda, Maryland.
Cancer Res. 2021 Jun 1;81(11):2903-2917. doi: 10.1158/0008-5472.CAN-20-3371. Epub 2021 Mar 8.
In nutrient-poor conditions, autophagy buffers metabolic stress and counteracts the effects of chemotherapy and radiation on cancer cells, which depend on autophagy for survival. However, clinical trials targeting autophagy have failed to produce successful anticancer treatments using currently available inhibitors. Recent studies have shown that PIKfyve kinase inhibitors disrupt lysosome function in autophagy and can selectively kill certain cancer cells. Analysis of biochemical changes caused by PIKfyve inhibition revealed that resistant cells contain significantly higher levels of cellular p38MAPK protein and phosphorylation. Expression of the lysosomal protein, lysosomal-associated membrane protein 2, carrying phosphomimetic mutations of the p38MAPK phosphorylation sites prevented all effects caused by PIKfyve inhibition-induced lysosome dysfunction. Thus, the activation of p38MAPK in response to PIKfyve inhibition revealed a novel compensatory role in maintaining lysosome function in autophagy. The functional cooperation between the cellular PIKfyve and p38MAPK pathways in regulating lysosome homeostasis was especially important in cancer cells. Combined inhibition of PIKfyve and p38MAPK activities synergistically blocked autophagy-mediated protein degradation, prevented cathepsin maturation, and markedly reduced the viability of multiple cancer cell types without affecting the viability of normal cells. Furthermore, combined PIKfyve and p38MAPK inhibitors synergistically reduced tumor growth in mice bearing xenografts of human colorectal adenocarcinoma, suggesting a novel way to target cancer cells by prolonged inhibition of autophagy using lower drug concentrations. SIGNIFICANCE: This study demonstrates that PIKfyve and p38MAPK cooperate to regulate lysosome homeostasis and their combined inhibition synergistically blocks autophagy to reduce cancer cell viability and .
在营养贫瘠的条件下，自噬缓冲代谢应激，并抵消化疗和放疗对癌细胞的作用，癌细胞依赖自噬生存。然而，靶向自噬的临床试验未能利用现有的抑制剂产生成功的抗癌治疗。最近的研究表明，PIKfyve 激酶抑制剂会破坏自噬中的溶酶体功能，并可以选择性地杀死某些癌细胞。对 PIKfyve 抑制引起的生化变化的分析表明，耐药细胞中含有显著更高水平的细胞 p38MAPK 蛋白和磷酸化。表达溶酶体蛋白溶酶体相关膜蛋白 2，携带 p38MAPK 磷酸化位点的磷酸模拟突变，可防止 PIKfyve 抑制诱导的溶酶体功能障碍引起的所有影响。因此，p38MAPK 的激活对 PIKfyve 抑制的反应揭示了在维持自噬中溶酶体功能方面的一种新的代偿作用。细胞 PIKfyve 和 p38MAPK 通路在调节溶酶体动态平衡方面的功能合作在癌细胞中尤为重要。PIKfyve 和 p38MAPK 活性的联合抑制协同阻断自噬介导的蛋白质降解，阻止组织蛋白酶成熟，并显著降低多种癌细胞类型的活力，而不影响正常细胞的活力。此外，联合使用 PIKfyve 和 p38MAPK 抑制剂协同减少了携带人结直肠腺癌异种移植物的小鼠的肿瘤生长，表明通过使用较低的药物浓度延长自噬抑制来靶向癌细胞的一种新方法。意义：本研究表明，PIKfyve 和 p38MAPK 合作调节溶酶体动态平衡，它们的联合抑制协同阻断自噬以降低癌细胞活力。
