AKT1 Is Required for a Complete Palbociclib-Induced Senescence Phenotype in BRAF-V600E-Driven Human Melanoma.
AKT1 Is Required for a Complete Palbociclib-Induced Senescence Phenotype in BRAF-V600E-Driven Human Melanoma.
复制标题
DOI：
10.3390/cancers14030572
复制
发表时间：
2022-01-23
期刊：
影响因子：
5.2
通讯作者：
Hinds PW
中科院分区：
文献类型：
--
作者：
Bayer AL;Pietruska J;Farrell J;McRee S;Alcaide P;Hinds PW
癌症的标志之一是细胞增殖增加;因此，许多治疗策略旨在阻止细胞分裂。几种化疗药物，包括CDK 4/6抑制剂（CDK 4/6 i），导致细胞衰老，其中细胞不可逆地停止增殖并经历许多功能变化。然而，某些形式的衰老会导致释放可能恶化癌症进展的因子。AKT基因家族是细胞增殖和衰老的主要调节因子;因此，我们试图研究对CDK 4/6 i的衰老应答中的三种AKT同种型中的每一种。我们发现，只有AKT 1是由CDK 4/6 i诱导的完全衰老表型所必需的，CDK 4/6 i通过NF-κB途径起作用。这项研究表明，靶向AKT 1与CDK 4/6 i的组合代表了一种治疗策略，其中可以在不释放促癌因子的情况下实现细胞衰老。 细胞衰老是一个精心调控的增殖停滞过程，伴随着功能和形态的变化。衰老允许受损细胞避免肿瘤增殖;然而，衰老相关分泌表型（SASP）的诱导可促进肿瘤生长。衰老的复杂性可能会限制抗肿瘤药物的疗效，如CDK 4/6抑制剂（Cdk 4/6 i），诱导肿瘤细胞的衰老样状态。AKT激酶家族包含在癌症进展中发挥独特和冗余作用的三种同种型，通常在包括黑色素瘤在内的许多癌症中过度活跃，并且与衰老的调节有关。为了探究AKT同种型在Cdk 4/6 i诱导的细胞衰老中的作用，我们产生了同种型特异性AKT敲除的人黑素瘤细胞系。我们发现，CDK 4/6 i Palbociclib在这些细胞中诱导了一种依赖于AKT 1的衰老形式。然后，我们评估了最近与细胞衰老有关的cGAS-STING途径的活性，发现cGAS-STING功能依赖于AKT 1，并且cGAS的药理学抑制对衰老几乎没有影响。然而，我们发现SASP因子需要NF-κB功能，部分依赖于AKT 1刺激IKKα磷酸化。总之，我们提供了AKT 1在治疗诱导的人黑色素瘤细胞衰老中通过NF-κB起作用但不依赖于cGAS的新型亚型特异性作用的第一个证据。
One of the hallmarks of cancer is increased cellular proliferation; therefore, many therapeutic strategies aim at arresting cellular division. Several chemotherapeutic drugs, including CDK4/6 inhibitors (CDK4/6i), result in cellular senescence, in which cells irreversibly stop proliferating and undergo many changes in function. However, some forms of senescence result in the release of factors that can worsen cancer progression. The AKT family of genes are a major regulator of cellular proliferation and senescence; therefore, we sought to study each of the three AKT isoforms in the senescence response to CDK4/6i. We found that only AKT1 is required for a full senescence phenotype induced by CDK4/6i, which works through the NF-κB pathway. This study suggests that targeting AKT1 in combination with CDK4/6i represents a therapeutic strategy in which cellular senescence can be achieved without the release of pro-cancer factors. Cellular senescence is a carefully regulated process of proliferative arrest accompanied by functional and morphologic changes. Senescence allows damaged cells to avoid neoplastic proliferation; however, the induction of the senescence-associated secretory phenotype (SASP) can promote tumor growth. The complexity of senescence may limit the efficacy of anti-neoplastic agents, such as CDK4/6 inhibitors (Cdk4/6i), that induce a senescence-like state in tumor cells. The AKT kinase family, which contains three isoforms that play both unique and redundant roles in cancer progression, is commonly hyperactive in many cancers including melanoma and has been implicated in the regulation of senescence. To interrogate the role of AKT isoforms in Cdk4/6i-induced cellular senescence, we generated isoform-specific AKT knockout human melanoma cell lines. We found that the CDK4/6i Palbociclib induced a form of senescence in these cells that was dependent on AKT1. We then evaluated the activity of the cGAS-STING pathway, recently implicated in cellular senescence, finding that cGAS-STING function was dependent on AKT1, and pharmacologic inhibition of cGAS had little effect on senescence. However, we found SASP factors to require NF-κB function, in part dependent on a stimulatory phosphorylation of IKKα by AKT1. In summary, we provide the first evidence of a novel, isoform-specific role for AKT1 in therapy-induced senescence in human melanoma cells acting through NF-κB but independent of cGAS.
登录
查看更多内容
DOI：
10.1158/1541-7786.mcr-20-0915
发表时间：
2021-05
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Gadsden NJ;Fulcher CD;Li D;Shrivastava N;Thomas C;Segall JE;Prystowsky MB;Schlecht NF;Gavathiotis E;Ow TJ
通讯作者：
Ow TJ
影响因子：
6.4
作者：
Bai, Dong;Ueno, Lynn;Vogt, Peter K.
通讯作者：
Vogt, Peter K.
影响因子：
3.7
作者：
HAYFLICK, L;MOORHEAD, PS
通讯作者：
MOORHEAD, PS
影响因子：
10.5
作者：
Chien, Yuchen;Scuoppo, Claudio;Lowe, Scott W.
通讯作者：
Lowe, Scott W.
影响因子：
21.3
作者：
Glück S;Guey B;Gulen MF;Wolter K;Kang TW;Schmacke NA;Bridgeman A;Rehwinkel J;Zender L;Ablasser A
通讯作者：
Ablasser A