Parathyroid hormone-related protein regulates cell survival pathways via integrin alpha6beta4-mediated activation of phosphatidylinositol 3-kinase/Akt signaling.
Parathyroid hormone-related protein regulates cell survival pathways via integrin alpha6beta4-mediated activation of phosphatidylinositol 3-kinase/Akt signaling.
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DOI：
10.1158/1541-7786.mcr-08-0568
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发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Falzon M
中科院分区：
文献类型：
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作者：
Bhatia V;Mula RV;Weigel NL;Falzon M
甲状旁腺相关蛋白（PTHrP）在人前列腺组织和癌细胞系中表达。PTHrP在体内促进肿瘤细胞生长和转移，在体外上调促侵袭性整合素α6β4表达。恶性肿瘤细胞的特征包括对凋亡的抗性和不依赖于锚定的细胞生长。在这项研究中，我们使用人前列腺癌细胞系C4-2和PC-3作为模型系统，研究PTHrP对这些过程的影响。我们报告PTHrP保护这些细胞免受阿霉素诱导的凋亡，并通过内分泌途径促进锚定非依赖性细胞生长。相反，自分泌/旁分泌PTHrP作用增加C4-2细胞的凋亡，而对PC-3细胞的凋亡没有影响。PTHrP对细胞凋亡的内分泌作用是通过激活磷脂酰肌醇3-激酶（PI 3-K）/Akt途径介导的。PTHrP还影响涉及凋亡抑制的Akt底物的磷酸化状态，包括糖原合成酶激酶-3和Bad。PTHrP的促存活作用伴随着Bcl-2家族的抗凋亡与促凋亡成员的比率和c-myc水平的增加。PTHrP还通过PI 3-K依赖性途径增加NF-κB活性。已知整合素α6β4激活PI 3-K。在这里，我们还表明，敲低整合素α6β4否定PTHrP介导的PI 3-K/Akt通路的激活。综上所述，这些观察结果提供了PTHrP和PI 3-K/Akt信号通路之间通过整合素α6β4的联系的证据，导致存活通路的激活。因此，靶向前列腺癌中PTHrP的产生可能证明是有益的。
Parathyroid hormone-related protein (PTHrP) is expressed by human prostatic tissues and cancer cell lines. PTHrP enhances tumor cell growth and metastasis in vivo and upregulates pro-invasive integrin α6β4 expression in vitro. Hallmarks of malignant tumor cells include resistance to apoptosis and anchorage-independent cell growth. In this study, we used the human prostate cancer cell lines C4-2 and PC-3 as model systems to study the effects of PTHrP on these processes. We report that PTHrP protects these cells from doxorubicin-induced apoptosis and promotes anchorage-independent cell growth via an intracrine pathway. Conversely, autocrine/paracrine PTHrP action increases apoptosis in C4-2 cells and has no effect on apoptosis in PC-3 cells. The intracrine effects of PTHrP on apoptosis are mediated via activation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. PTHrP also affects the phosphorylation state of Akt substrates implicated in apoptosis suppression, including glycogen synthase kinase-3 and Bad. The pro-survival effects of PTHrP are accompanied by increases in the ratio of anti- to pro-apoptosis members of the Bcl-2 family and in levels of c-myc. PTHrP also increases NF-κB activity via a PI3-K-dependent pathway. Integrin α6β4 is known to activate PI3-K. Here we also show that knockdown of integrin α6β4 negates the PTHrP-mediated activation of the PI3-K/Akt pathway. Taken together, these observations provide evidence of a link between PTHrP and the PI3-K/Akt signaling pathway through integrin α6β4, resulting in the activation of survival pathways. Targeting PTHrP production in prostate cancer may thus prove therapeutically beneficial.