PAK Research Center, Melbourne, Australia.
Melbourne University Hospital (Austin Health), Melbourne, Australia.
Drug Discov Ther. 2024 Jun 6;18(2):134-139. doi: 10.5582/ddt.2023.01097. Epub 2024 Apr 4.
Both PAK1 (RAC/CDC42-activating kinase 1) and TOR (Target of Rapamycin) are among the major oncogenic/ageing kinases. However, they play the opposite role in our immune system, namely immune system is suppressed by PAK1, while it requires TOR. Thus, PAK1-blockers, would be more effective for therapy of cancers, than TOR-blockers. Since 2015 when we discovered genetically that PDGF-induced melanogenesis depends on "PAK1", we are able to screening a series of PAK1-blockers as melanogenesis-inhibitors which could eventually promote longevity. Interestingly, rapamycin, the first TOR-inhibitor, promotes melanogenesis, clearly indicating that TOR suppresses melanogenesis. However, a new TOR-inhibitor called TORin-1 no longer suppresses immune system, and blocks melanogenesis in cell culture. These observations strongly indicate that TORin-1 acts as PAK1-blockers, instead of TOR-blockers, in vivo. Thus, it is most likely that melanogenesis in cell culture could enable us to discriminate PAK1-blockers from TORblockers.
PAK1（RAC/CDC42 激活激酶 1）和 TOR（雷帕霉素靶蛋白）都是主要的致癌/衰老激酶。然而，它们在我们的免疫系统中扮演着相反的角色，即免疫系统被 PAK1 抑制，而需要 TOR。因此，PAK1 抑制剂在癌症治疗方面比 TOR 抑制剂更有效。自 2015 年我们从遗传学上发现 PDGF 诱导的黑色素生成依赖于“PAK1”以来，我们能够筛选一系列作为黑色素生成抑制剂的 PAK1 抑制剂，最终可能促进长寿。有趣的是，雷帕霉素，即第一种 TOR 抑制剂，促进黑色素生成，这清楚地表明 TOR 抑制黑色素生成。然而，一种新的 TOR 抑制剂 TORin-1 不再抑制免疫系统，并在细胞培养中阻断黑色素生成。这些观察结果强烈表明，TORin-1 在体内作为 PAK1 抑制剂，而不是 TOR 抑制剂。因此，细胞培养中的黑色素生成很可能使我们能够区分 PAK1 抑制剂和 TOR 抑制剂。
