Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor.
Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor.
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DOI：
10.1016/j.cell.2015.01.001
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发表时间：
2015-01-29
期刊：
影响因子：
64.5
通讯作者：
Newton AC
中科院分区：
文献类型：
--
作者：
Antal CE;Hudson AM;Kang E;Zanca C;Wirth C;Stephenson NL;Trotter EW;Gallegos LL;Miller CJ;Furnari FB;Hunter T;Brognard J;Newton AC
蛋白激酶C（PKC）同工酶仍然难以捉摸的癌症目标，尽管明确的肿瘤促进功能的有效配体，佛波酯，和他们的突变的患病率。我们分析了在人类癌症中发现的8%的PKC突变，令人惊讶的是，大多数是功能丧失，没有激活。失功能突变发生在所有的PKC亚组，并阻碍第二信使结合，磷酸化，或催化。通过CRISPR介导的基因组编辑在患者来源的结肠癌细胞系中校正功能丧失的PKCβ突变抑制了异种移植模型中的锚定非依赖性生长并减少了肿瘤生长。半合子缺失促进了锚定非依赖性生长，表明PKCβ单倍不足抑制肿瘤。几个突变是显性负性的，抑制了整体PKC信号输出，生物信息学分析表明，PKC突变与癌症驱动因素中的共现突变合作。这些数据表明，PKC同工酶通常作为肿瘤抑制因子发挥作用，这表明治疗应侧重于恢复而不是抑制PKC活性。
Protein kinase C (PKC) isozymes have remained elusive cancer targets despite the unambiguous tumor promoting function of their potent ligands, phorbol esters, and the prevalence of their mutations. We analyzed 8% of PKC mutations identified in human cancers and found that, surprisingly, most were loss of function and none were activating. Loss-of-function mutations occurred in all PKC subgroups and impeded second-messenger binding, phosphorylation, or catalysis. Correction of a loss-of-function PKCβ mutation by CRISPR-mediated genome editing in a patient-derived colon cancer cell line suppressed anchorage-independent growth and reduced tumor growth in a xenograft model. Hemizygous deletion promoted anchorage-independent growth, revealing that PKCβ is haploinsufficient for tumor suppression. Several mutations were dominant negative, suppressing global PKC signaling output, and bioinformatic analysis suggested that PKC mutations cooperate with co-occurring mutations in cancer drivers. These data establish that PKC isozymes generally function as tumor suppressors, indicating that therapies should focus on restoring, not inhibiting, PKC activity.
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