Transient arrest in a quiescent state allows ovarian cancer cells to survive suboptimal growth conditions and is mediated by both Mirk/dyrk1b and p130/RB2
Transient arrest in a quiescent state allows ovarian cancer cells to survive suboptimal growth conditions and is mediated by both Mirk/dyrk1b and p130/RB2
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DOI：
10.1002/ijc.25692
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发表时间：
2011-07-15
影响因子：
6.4
通讯作者：
Friedman, Eileen
中科院分区：
文献类型：
--
作者：
Hu, Jing;Nakhla, Hassan;Friedman, Eileen
一些卵巢癌细胞在体内处于可逆的静止状态，在有利的生长条件下，它们可以促进癌症扩散。丝氨酸/苏氨酸激酶Mirk/dyrk 1B在7个卵巢癌细胞系和28个切除的人卵巢癌中的21个中表达，并且在60%的癌症中上调。一些卵巢癌细胞被发现处于G 0静止状态，在具有扩增的Mirk基因的细胞系中比例最高。次优培养条件增加了SKOV 3和TOV 21 G培养物中的G 0分数，但不增加OVCAR 4培养物中的G 0分数。如通过总细胞数、染料排除活力研究和裂解的凋亡标志物蛋白的测定所示，在次优培养条件下存活的OVCAR 4细胞少于一半。TOV 21 G和SKOV 3细胞中的G 0阻滞导致Mirk、CDK抑制剂p27、p130/Rb 2和与E2 F4复合的p130/Rb 2水平增加。G 0停滞是短暂的，当供应新鲜营养时，细胞退出G 0。耗尽p130/Rb 2减少G 0分数，增加细胞对无血清培养和顺铂的敏感性，并降低Mirk水平。Mirk通过使细胞周期蛋白D1不稳定而导致G 0期阻滞。在TOV 21 G细胞中，而不是在正常二倍体成纤维细胞中，Mirk耗竭导致细胞凋亡增加和活力丧失。由于Mirk在大多数正常成人组织中以低水平表达，因此卵巢癌中升高的Mirk蛋白水平可能是一种新的治疗靶点，特别是对于难以通过靶向分裂细胞的常规疗法根除的静止肿瘤细胞。
Some ovarian cancer cells in vivo are in a reversible quiescent state where they can contribute to cancer spread under favorable growth conditions. The serine/threonine kinase Mirk/dyrk1B was expressed in each of seven ovarian cancer cell lines and in 21 of 28 resected human ovarian cancers, and upregulated in 60% of the cancers. Some ovarian cancer cells were found in a G0 quiescent state, with the highest fraction in a line with an amplified Mirk gene. Suboptimal culture conditions increased the G0 fraction in SKOV3 and TOV21G, but not OVCAR4 cultures. Less than half as many OVCAR4 cells survived under suboptimal culture conditions as shown by total cell numbers, dye exclusion viability studies, and assay of cleaved apoptotic marker proteins. G0 arrest in TOV21G and SKOV3 cells led to increased levels of Mirk, the CDK inhibitor p27, p130/Rb2, and p130/Rb2 complexed with E2F4. The G0 arrest was transient, and cells exited G0 when fresh nutrients were supplied. Depletion of p130/Rb2 reduced the G0 fraction, increased cell sensitivity to serum-free culture and to cisplatin, and reduced Mirk levels. Mirk contributed to G0 arrest by destabilization of cyclin D1. In TOV21G cells, but not in normal diploid fibroblasts, Mirk depletion led to increased apoptosis and loss of viability. Because Mirk is expressed at low levels in most normal adult tissues, the elevated Mirk protein levels in ovarian cancers may present a novel therapeutic target, in particular for quiescent tumor cells which are difficult to eradicate by conventional therapies targeting dividing cells.