National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Room 6N105, 10 Center Dr., Bethesda, MD 20892-0001, USA.
National Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Room 4B413, 6 Center Dr., Bethesda, MD 20892-2790, USA.
Cells. 2024 Jun 25;13(13):1096. doi: 10.3390/cells13131096.
The goal of cancer research is to identify characteristics of cancer cells that allow them to be selectively eliminated without harming the host. One such characteristic is autophagy dependence. Cancer cells survive, proliferate, and metastasize under conditions where normal cells do not. Thus, the requirement in cancer cells for more energy and macromolecular biosynthesis can evolve into a dependence on autophagy for recycling cellular components. Recent studies have revealed that autophagy, as well as different forms of cellular trafficking, is regulated by five phosphoinositides associated with eukaryotic cellular membranes and that the enzymes that synthesize them are prime targets for cancer therapy. For example, PIKFYVE inhibitors rapidly disrupt lysosome homeostasis and suppress proliferation in all cells. However, these inhibitors selectively terminate PIKFYVE-dependent cancer cells and cancer stem cells with not having adverse effect on normal cells. Here, we describe the biochemical distinctions between PIKFYVE-sensitive and -insensitive cells, categorize PIKFYVE inhibitors into four groups that differ in chemical structure, target specificity and efficacy on cancer cells and normal cells, identify the mechanisms by which they selectively terminate autophagy-dependent cancer cells, note their paradoxical effects in cancer immunotherapy, and describe their therapeutic applications against cancers.
癌症研究的目标是识别使癌细胞能够被选择性消除而不伤害宿主的特征。其中一个特征是自噬依赖性。在正常细胞无法生存、增殖和转移的情况下，癌细胞能够存活、增殖和转移。因此，癌细胞对更多能量和大分子生物合成的需求可能演变成对自噬的依赖，以回收细胞成分。最近的研究表明，自噬以及不同形式的细胞运输都受到与真核细胞膜相关的五种磷酸肌醇的调节，合成它们的酶是癌症治疗的主要靶点。例如，PIKFYVE 抑制剂可迅速破坏溶酶体平衡并抑制所有细胞的增殖。然而，这些抑制剂选择性地终止 PIKFYVE 依赖性癌细胞和癌细胞干细胞，而对正常细胞没有不良影响。在这里，我们描述了 PIKFYVE 敏感和不敏感细胞之间的生化差异，将 PIKFYVE 抑制剂分为四类，它们在化学结构、靶标特异性和对癌细胞和正常细胞的疗效上有所不同，确定了它们选择性终止自噬依赖性癌细胞的机制，注意到它们在癌症免疫治疗中的矛盾作用，并描述了它们在癌症治疗中的应用。
