Ack1 Tyrosine Kinase Activation Correlates with Pancreatic Cancer Progression
Ack1 Tyrosine Kinase Activation Correlates with Pancreatic Cancer Progression
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DOI：
10.1016/j.ajpath.2011.12.028
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发表时间：
2012-04-01
影响因子：
6
通讯作者：
Mahajan, Nupam P.
中科院分区：
文献类型：
--
作者：
Mahajan, Kiran;Coppola, Domenico;Mahajan, Nupam P.
胰腺癌是世界范围内癌症死亡率的重要原因，因为该疾病在症状明显之前已经在患者中显著进展。促进这种快速进展的信号转导途径还不清楚。Ack 1或TNK 2是一种广泛表达的致癌性非受体酪氨酸激酶，整合来自配体激活的受体酪氨酸激酶的信号以调节细胞内信号级联。在本研究中，我们研究了胰腺癌肿瘤微阵列中的Ack 1激活谱，并观察到激活的Ack 1和pTyr 284-Ack 1的表达水平与疾病进展的严重程度呈正相关，与胰腺癌患者的生存率呈负相关。为了探索Ack 1促进肿瘤进展的机制，我们研究了AKT/PKB（一种癌基因和Ack 1相互作用蛋白）的作用。Ack 1通过在Tyr 176磷酸化AKT来直接激活胰腺癌和其他癌细胞系中的AKT，以促进细胞存活。此外，Ack 1抑制剂AIM-100不仅抑制Ack 1活化，而且抑制AKT酪氨酸磷酸化，导致细胞周期停滞在G1期。这种作用导致胰腺癌细胞增殖的显著降低和凋亡的诱导。总的来说，我们的数据表明激活的Ack 1可能是确定早期或晚期胰腺癌的预后标志物。因此，Ack 1抑制剂有望用于治疗干预以抑制胰腺肿瘤生长。(Am J Pathol 2012，180：1386-1393; DOI：10.1016/j.ajpath.2011.12.028）
Pancreatic cancer is a significant cause of cancer mortality worldwide as the disease has advanced significantly in patients before symptoms are evident. The signal transduction pathways that promote this rapid progression are not well understood. Ack1 or TNK2, an ubiquitously expressed oncogenic non receptor tyrosine kinase, integrates signals from ligand-activated receptor tyrosine kinases to modulate intracellular signaling cascades. In the present study, we investigated the Ack1 activation profile in a pancreatic cancer tumor microarray, and observed that expression levels of activated Ack1 and pTyr284-Ack1 positively correlated with the severity of disease progression and inversely correlated with the survival of patients with pancreatic cancer. To explore the mechanisms by which Ack1 promotes tumor progression, we investigated the role of AKT/PKB, an oncogene and Ack1-interacting protein. Ack1 activates AKT directly in pancreatic and other cancer cell lines by phosphorylating AKT at Tyr176 to promote cell survival. In addition, the Ack1 inhibitor AIM-100 not only inhibited Ack1 activation but also suppressed AKT tyrosine phosphorylation, leading to cell cycle arrest in the G1 phase. This effect resulted in a significant decrease in the proliferation of pancreatic cancer cells and induction of apoptosis. Collectively, our data indicate that activated Ack1 could be a prognostic marker for ascertaining early or advanced pancreatic cancer. Thus, Ack1 inhibitors hold promise for therapeutic intervention to inhibit pancreatic tumor growth. (Am J Pathol 2012, 180:1386-1393; DOI: 10.1016/j.ajpath.2011.12.028)