Concomitant targeting of EGF receptor, TGF-beta and SRC points to a novel therapeutic approach in pancreatic cancer.
Concomitant targeting of EGF receptor, TGF-beta and SRC points to a novel therapeutic approach in pancreatic cancer.
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DOI：
10.1371/journal.pone.0039684
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Korc M
中科院分区：
文献类型：
--
作者：
Deharvengt S;Marmarelis M;Korc M
为了验证同时靶向表皮生长因子受体（EGFR）和转化生长因子-β (TGF-β)可能为胰腺癌提供一种新的治疗方法的假设，我们将RNA干扰（shEGFR）沉默EGFR与可溶性TGF-β受体II （st -β rii）隔离TGF-β结合起来。监测其对三维培养中菌落形成、裸鼠肿瘤形成和下游信号传导的影响。在ASPC-1和T3M4细胞中，shEGFR或st - β rii均显著抑制集落形成。然而，在ASPC-1细胞中，将shEGFR与st - β rii联合使用比单独使用任何一种方法都更有效地减少了集落形成，而在T3M4细胞中，st - β rii逆转了shEGFR介导的集落形成抑制。同样，shEGFR或st - β rii均能抑制aspc -1源性肿瘤的体内生长，两种载体均能显著抑制肿瘤生长。相比之下，当EGFR单独沉默时，t3m4衍生的肿瘤要么无法形成，要么非常小，由于癌细胞增殖增加，这些作用被sTβRII逆转。shEGFR和sTβRII联合使用可降低ASPC-1细胞中phospho-HER2、phospho-HER3、phospho- erk和phospho-src （Tyr416）的水平，而在T3M4细胞中升高。此外，拉帕替尼对EGFR和HER2的抑制，或SSKI-606、PP2或达沙替尼对src的抑制，阻断了stβ rii介导的T3M4细胞中集落形成的拮抗作用。总之，这些观察结果表明，同时靶向EGFR、TGF-β和src可能构成一种新的PDAC治疗方法，可以防止EGFR家族成员和TGF-β依赖通路之间的有害串扰。
To test the hypothesis that concomitant targeting of the epidermal growth factor receptor (EGFR) and transforming growth factor-beta (TGF-β) may offer a novel therapeutic approach in pancreatic cancer, EGFR silencing by RNA interference (shEGFR) was combined with TGF-β sequestration by soluble TGF-β receptor II (sTβRII). Effects on colony formation in 3-dimensional culture, tumor formation in nude mice, and downstream signaling were monitored. In both ASPC-1 and T3M4 cells, either shEGFR or sTβRII significantly inhibited colony formation. However, in ASPC-1 cells, combining shEGFR with sTβRII reduced colony formation more efficiently than either approach alone, whereas in T3M4 cells, shEGFR-mediated inhibition of colony formation was reversed by sTβRII. Similarly, in vivo growth of ASPC-1-derived tumors was attenuated by either shEGFR or sTβRII, and was markedly suppressed by both vectors. By contrast, T3M4-derived tumors either failed to form or were very small when EGFR alone was silenced, and these effects were reversed by sTβRII due to increased cancer cell proliferation. The combination of shEGFR and sTβRII decreased phospho-HER2, phospho-HER3, phoshpo-ERK and phospho-src (Tyr416) levels in ASPC-1 cells but increased their levels in T3M4 cells. Moreover, inhibition of both EGFR and HER2 by lapatinib or of src by SSKI-606, PP2, or dasatinib, blocked the sTβRII-mediated antagonism of colony formation in T3M4 cells. Together, these observations suggest that concomitantly targeting EGFR, TGF-β, and src may constitute a novel therapeutic approach in PDAC that prevents deleterious cross-talk between EGFR family members and TGF-β-dependent pathways.
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酪氨酸激酶 c-Src 直接介导胰腺癌细胞中生长因子诱导的 Notch-1 和 Furin 相互作用以及 Notch-1 激活。
影响因子：
3.7
作者：
Ma YC;Shi C;Zhang YN;Wang LG;Liu H;Jia HT;Zhang YX;Sarkar FH;Wang ZS
通讯作者：
Wang ZS
SRC激酶和表皮生长因子受体与吉西他滨的结合阻断了STAT3介导的胰腺肿瘤生长抑制的耐药性。
DOI：
10.1158/1078-0432.ccr-10-1670
发表时间：
2011-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Nagaraj NS;Washington MK;Merchant NB
通讯作者：
Merchant NB
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3
作者：
Korc, Murray
通讯作者：
Korc, Murray
影响因子：
9
作者：
Lim, JE;Chien, MW;Earle, CC
通讯作者：
Earle, CC