Targeting tyrosine kinases and autophagy in prostate cancer.
Targeting tyrosine kinases and autophagy in prostate cancer.
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靶向前列腺癌中酪氨酸激酶和自噬。
DOI：
10.1007/s12672-010-0053-3
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发表时间：
2011-02
影响因子：
3
通讯作者：
Kung HJ
中科院分区：
文献类型：
--
作者：
Kung HJ
酪氨酸激酶在肿瘤进展和治疗抗性中起重要作用。酪氨酸激酶抑制剂是靶向治疗的前沿。对于前列腺癌，酪氨酸激酶在去势抵抗性疾病状态的发展中发挥额外的作用，去势抵抗性疾病状态是目前无法进行任何有效治疗的前列腺增生的最令人不安的方面。在典型的前列腺癌细胞中表达的约30种酪氨酸激酶中，近三分之一与前列腺癌发生有关。有趣的是，它们中的大多数通过三种非受体酪氨酸激酶Src/Etk/FAK（这里称为Src酪氨酸激酶复合物）来传递信号。该复合物已显示在由生长因子（例如，表皮生长因子（EGF））、细胞因子（白细胞介素（IL）-6）、趋化因子（IL-8）和神经因子（胃泌素释放肽）。这些因子在雄激素戒断时被诱导并从前列腺癌释放到基质细胞。Src激酶复合物具有使雄激素受体磷酸化的能力，导致未配体的雄激素受体的核转位和稳定。事实上，靶向Src的酪氨酸激酶抑制剂可以在体外和临床前异种移植模型中抑制前列腺癌细胞的雄激素非依赖性生长。虽然Src抑制剂在诱导去势抵抗性肿瘤的生长停滞和抑制转移方面有效，但很少诱导显著水平的细胞凋亡。这也反映在临床试验中酪氨酸激酶抑制剂作为单药治疗的一般无效性上。细胞凋亡抗性的根本原因之一是“自噬”，其由酪氨酸激酶抑制剂和雄激素戒断诱导。自噬是一种自我消化的过程，通过去除长寿命的蛋白质和退休的细胞器来再生能量，从而为遇到压力的细胞提供生存机制。过度的自噬有时会导致II型程序性细胞死亡。我们证明了自噬阻断使前列腺癌细胞对Src酪氨酸激酶抑制剂敏感。因此，基于Src酪氨酸激酶抑制剂和自噬调节剂的联合治疗作为复发性前列腺癌的潜在治疗值得进一步关注。
Tyrosine kinases play significant roles in tumor progression and therapy resistance. Inhibitors of tyrosine kinases are on the forefront of targeted therapy. For prostate cancer, tyrosine kinases play an additional role in the development of castration-resistant disease state, the most troubling aspect of prostate cancinogenesis which presently defies any effective treatment. Among the 30 or so tyrosine kinases expressed in a typical prostate cancer cell, nearly one third of them have been implicated in prostate carcinogenesis. Interestingly, most of them channel signals through a trio of non-receptor tyrosine kinases, Src/Etk/FAK, referred here as Src tyrosine kinase complex. This complex has been shown to play a significant role in the aberrant activation of androgen receptor (AR) mediated by growth factors (e.g., epidermal growth factor (EGF)), cytokines (interleukin (IL)-6), chemokines (IL-8), and neurokines (gastrin-releasing peptide). These factors are induced and released from the prostate cancer to the stromal cells upon androgen withdrawal. The Src kinase complex has the ability to phosphorylate androgen receptor, resulting in the nuclear translocation and stabilization of un-liganded androgen receptor. Indeed, tyrosine kinase inhibitors targeting Src can inhibit androgen-independent growth of prostate cancer cells in vitro and in preclinical xenograft model. While effective in inducing growth arrest and inhibiting metastasis of castration-resistant tumors, Src inhibitors rarely induce a significant level of apoptosis. This is also reflected by the general ineffectiveness of tyrosine kinase inhibitors as monotherapy in clinical trials. One of the underlying causes of apoptosis resistance is “autophagy,” which is induced by tyrosine kinase inhibitors and by androgen withdrawal. Autophagy is a self-digesting process to regenerate energy by removal of long-lived proteins and retired organelles to provide a survival mechanism to cells encountering stresses. Excessive autophagy, sometimes, could lead to type II programmed cell death. We demonstrated that autophagy blockade sensitizes prostate cancer cells toward Src tyrosine kinase inhibitor. Thus, a combination therapy based on Src tyrosine kinase inhibitor and autophagy modulator deserves further attention as a potential treatment for relapsed prostate cancer.