Yokoi Kenji, Fidler Isaiah J
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2004 Apr 1;10(7):2299-306. doi: 10.1158/1078-0432.ccr-03-0488.
Hypoxia, frequently found in the center of solid tumor, is associated with resistance to chemotherapy by activation of signaling pathways that regulate cell pro-liferation, 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 kappa B (NF-kappa B) signaling pathways.
We evaluated the phosphorylation of Akt and MAPK(Erk), DNA binding activity of NF-kappa B, 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.
Hypoxic conditions increased phosphorylation of Akt and MAPK(Erk) and NF-kappa B DNA binding activity in L3.6pl cells. The activation of Akt and NF-kappa B was prevented by LY294002, whereas the activity of MAPK(Erk), but not NF-kappa B, was inhibited by U0126. The increased activation of Akt, NF-kappa B, 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.
These data demonstrate that hypoxia can induce resistance of pancreatic cancer cells to gemcitabine mainly through the PI3K/Akt/NF-kappa B pathways and partially through the MAPK(Erk) signaling pathway. Because PKI 166 prevented the activation of PI3K/Akt/NF-kappa B and MAPK(Erk) pathways, the combination of this tyrosine kinase inhibitor with gemcitabine should be an effective therapy for pancreatic cancer.
低氧常见于实体瘤中心，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耐药相关。我们确定低氧是否可通过激活磷脂酰肌醇3'-激酶（PI3K）/Akt、MEK/丝裂原活化蛋白激酶（细胞外信号调节激酶）[MAPK（Erk）激酶（MEK）]和核因子κB（NF-κB）信号通路来增加人胰腺癌细胞对吉西他滨诱导凋亡的耐药性。
我们评估了常氧和低氧条件下L3.6pl人胰腺癌细胞中Akt和MAPK（Erk）的磷酸化、NF-κB的DNA结合活性以及吉西他滨诱导的凋亡。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对这些信号通路和凋亡诱导的影响。
低氧条件增加了L3.6pl细胞中Akt和MAPK（Erk）的磷酸化以及NF-κB的DNA结合活性。LY294002可阻止Akt和NF-κB的激活，而U0126可抑制MAPK（Erk）的活性，但不能抑制NF-κB的活性。PKI 166可抑制Akt、NF-κB和MAPK（Erk）激活的增加。在低氧条件下，L3.6pl细胞对吉西他滨诱导的凋亡具有耐药性。添加LY294002或PKI 166可消除细胞对吉西他滨的耐药性，而U0126仅部分降低这种耐药性。
这些数据表明，低氧可主要通过PI3K/Akt/NF-κB通路并部分通过MAPK（Erk）信号通路诱导胰腺癌细胞对吉西他滨产生耐药性。由于PKI 166可阻止PI3K/Akt/NF-κB和MAPK（Erk）通路的激活，这种酪氨酸激酶抑制剂与吉西他滨联合应用应是治疗胰腺癌的有效方法。
