Enhanced Sensitivity of Pancreatic Cancer Cells to Concurrent Inhibition of Aberrant Signal Transducer and Activator of Transcription 3 and Epidermal Growth Factor Receptor or Src
Enhanced Sensitivity of Pancreatic Cancer Cells to Concurrent Inhibition of Aberrant Signal Transducer and Activator of Transcription 3 and Epidermal Growth Factor Receptor or Src
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DOI：
10.1124/jpet.109.162669
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发表时间：
2010-05-01
影响因子：
3.5
通讯作者：
Turkson, James
中科院分区：
文献类型：
--
作者：
Jaganathan, Soumya;Yue, Peibin;Turkson, James
胰腺癌中存在许多分子异常。虽然异常的表皮生长因子受体(EGFR)、Src和信号转导和转录激活因子3(STAT3)与胰腺癌有关，但仅针对其中一个实体的治疗受到信号串扰的破坏。在人胰腺癌细胞系中，PANC-1和COLO-357、pY845EGFR、pY1068EGFR、pY1086EGFR和pY1173EGFR的表达水平和pY416c-Src的表达水平与异常激活的STAT3在复杂的信号串扰中同时升高。因此，了解信号整合将有助于设计有效的多靶点治疗方式。在PANC-1和COLO-357细胞中，pY845EGFR、pY1068EGFR和pY1086EGFR水平对c-Src抑制有反应，而pY1173EGFR则依赖于EGFR激酶。固有活性的STAT3对EGFR和Src的抑制都很敏感，但EGFR和Src抑制对异常活性的STAT3的早期抑制可以被Janus Kinase(JAKS)依赖的重新激活所抵消，这表明JAKS活性是STAT3诱导的一种代偿机制。单独抑制EGFR、Src或STAT3可引起较弱的生物学反应。相反，同时抑制STAT3和EGFR或Src可诱导胰腺癌细胞更大的活力丧失和凋亡，并减少胰腺癌细胞的迁移/侵袭。值得注意的是，与单一靶向方式相比，同时抑制方式在异种移植瘤中诱导了更强的人胰腺肿瘤生长抑制。我们推测，体内肿瘤的生长抑制是由于STAT3和EGFR或Src的异常功能同时被抑制所致。这些研究有力地表明，同时靶向STAT3和EGFR或Src可能是治疗胰腺癌的一种有益的方法。
Many molecular aberrations occur in pancreatic cancer. Although aberrant epidermal growth factor receptor (EGFR), Src, and signal transducer and activator of transcription 3 (Stat3) are implicated in pancreatic cancer, therapies that target only one of these entities are undermined by signaling cross-talk. In the human pancreatic cancer lines, Panc-1 and Colo-357, pY845EGFR, pY1068EGFR, pY1086EGFR, and pY1173EGFR levels and pY416c-Src are concurrently elevated with aberrantly active Stat3 in a complex signaling cross-talk. Thus, understanding the signaling integration would facilitate the design of effective multiple-targeted therapeutic modalities. In Panc-1 and Colo-357 lines, pY845EGFR, pY1068EGFR, and pY1086EGFR levels are responsive to c-Src inhibition in contrast to pY1173EGFR, which is EGFR kinase-dependent. Constitutively active Stat3 is sensitive to both EGFR and Src inhibition, but the early suppression of aberrantly active Stat3 in response to the inhibition of EGFR and Src is countered by a Janus kinase (Jaks)-dependent reactivation, suggesting that Jaks activity is a compensatory mechanism for Stat3 induction. The inhibition of EGFR, Src, or Stat3 alone induced weak biological responses. By contrast, the concurrent inhibition of Stat3 and EGFR or Src induced greater viability loss and apoptosis and decreased the migration/invasion of pancreatic cancer cells in vitro. Significantly, the concurrent inhibition, compared with monotargeting modality, induced stronger human pancreatic tumor growth inhibition in xenografts. We infer that the tumor growth inhibition in vivo is caused by the simultaneous suppression of the abnormal functions of Stat3 and EGFR or Src. These studies strongly suggest that the concurrent targeting of Stat3 and EGFR or Src could be a beneficial therapeutic approach for pancreatic cancer.