Hypoxia increases resistance of human pancreatic cancer cells to apoptosis induced by gemcitabine
Hypoxia increases resistance of human pancreatic cancer cells to apoptosis induced by gemcitabine
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DOI：
10.1158/1078-0432.ccr-03-0488
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发表时间：
2004-04-01
影响因子：
11.5
通讯作者：
Fidler, IJ
中科院分区：
文献类型：
--
作者：
Yokoi, K;Fidler, IJ
目的：常在实体瘤中心发现的缺氧通过激活调节细胞增殖、血管生成和凋亡的信号通路与化疗抗性相关。本研究通过激活磷脂酰肌醇3'-激酶（PI3K）/Akt、MEK/丝裂原活化蛋白激酶（MAPK），探讨缺氧是否能增加人胰腺癌细胞对吉西他滨诱导的凋亡的抵抗力。（细胞外信号调节激酶）[MAPK（Erk）激酶（MEK）]和核因子κ B（NF-kappaB）信号通路。我们评估了Akt和MAPK（Erk）的磷酸化，NF-κ B的DNA结合活性，以及在常氧和低氧条件下吉西他滨诱导L3.6pl人胰腺癌细胞凋亡。然后，我们研究了PI3K抑制剂LY294002，MEK抑制剂U0126和表皮生长因子受体酪氨酸激酶抑制剂PKI 166对这些信号通路和诱导apoptosis. Results的影响：低氧条件下增加Akt和MAPK（Erk）和NF-κ B DNA结合活性在L3.6pl细胞的磷酸化。LY294002可抑制Akt和NF-κ B的激活，而U0126可抑制MAPK（Erk）的活性，但不抑制NF-κ B的活性。Akt、NF-κ B和MAPK（Erk）的增加的活化被PKI 166抑制。在低氧条件下，L3.6pl细胞对吉西他滨诱导的凋亡具有抵抗性。LY294002或PKI 166的加入消除了细胞对吉西他滨的耐药性，而U0126仅部分降低了这种resistance.Conclusions：这些数据表明，缺氧可以诱导胰腺癌细胞对吉西他滨的耐药性主要通过PI3K/Akt/NF-κ B途径，部分通过MAPK（Erk）信号通路。由于PKI 166阻止了PI3K/Akt/NF-κ B和MAPK（Erk）通路的激活，因此这种酪氨酸激酶抑制剂与吉西他滨的组合应该是胰腺癌的有效治疗。
Purpose: Hypoxia, frequently found in the center of solid tumor, is associated with resistance to chemotherapy by activation of signaling pathways that regulate cell proliferation, angiogenesis, and apoptosis. We determined whether hypoxia can increase the resistance of human pancreatic carcinoma cells to gemcitabine-induced apoptosis by activation of phosphatidylinositol 3'-kinase (PI3K)/Akt, MEK/mitogen-activated protein kinase (extracellular signal-regulated kinase) [MAPK(Erk) kinase (MEK)], and nuclear factor kappaB (NF-kappaB) signaling pathways.Experimental Design: We evaluated the phosphorylation of Akt and MAPK(Erk), DNA binding activity of NF-kappaB, and apoptosis induced by gemcitabine in L3.6pl human pancreatic cancer cells under normoxic and hypoxic conditions. We then examined the effects of the PI3K inhibitor LY294002, MEK inhibitor U0126, and the epidermal growth factor receptor tyrosine kinase inhibitor PKI 166 on these signaling pathways and induction of apoptosis.Results: Hypoxic conditions increased phosphorylation of Akt and MAPK(Erk) and NF-kappaB DNA binding activity in L3.6pl cells. The activation of Akt and NF-kappaB was prevented by LY294002, whereas the activity of MAPK(Erk), but not NF-kappaB, was inhibited by U0126. The increased activation of Akt, NF-kappaB, and MAPK(Erk) was inhibited by PKI 166. Under hypoxic conditions, L3.6pl cells were resistant to apoptosis induced by gemcitabine. The addition of LY294002 or PKI 166 abrogated cell resistance to gemcitabine, whereas U0126 only partially decreased this resistance.Conclusions: These data demonstrate that hypoxia can induce resistance of pancreatic cancer cells to gemcitabine mainly through the PI3K/Akt/NF-kappaB pathways and partially through the MAPK(Erk) signaling pathway. Because PKI 166 prevented the activation of PI3K/Akt/NF-kappaB and MAPK(Erk) pathways, the combination of this tyrosine kinase inhibitor with gemcitabine should be an effective therapy for pancreatic cancer.