Caspase control: protagonists of cancer cell apoptosis.
Caspase control: protagonists of cancer cell apoptosis.
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发表时间：
2012-10
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通讯作者：
Michael V. Fiandalo;N. Kyprianou
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作者：
Michael V. Fiandalo;N. Kyprianou
去势抵抗性转移性前列腺癌的出现是由于生存途径的激活，包括细胞凋亡抑制和失巢凋亡抵抗，以及新血管形成的增加。因此，靶向细胞凋亡参与者在前列腺癌治疗中具有关键意义，因为细胞凋亡的丧失和对失巢凋亡的抗性在异常恶性生长、转移和赋予治疗失败中是关键的。大多数治疗剂通过内在线粒体、外在死亡受体途径或内质网应激途径起作用以诱导细胞凋亡。目前的治疗策略靶向恢复控制促存活途径的调节分子，如调节AKT活性的PTEN。其他策略集中于通过下调抗凋亡参与者如BCL-2或通过上调促凋亡蛋白家族（最值得注意的是半胱天冬酶）来重新激活凋亡途径。半胱天冬酶是胱氨酸蛋白酶家族，在细胞凋亡和炎症信号通路中起关键作用。在肿瘤发生过程中，caspase家族中主要成员的显著丢失或失活导致细胞凋亡诱导受损，导致生长动力学的显著失衡，最终导致人类癌症的异常生长。最近开发的细胞凋亡途径恢复凋亡诱导通过半胱天冬酶再激活提供了新的分子平台，有效地针对晚期前列腺癌以及其他实体瘤的治疗策略的发展。这篇综述将讨论目前的细胞景观具有caspase家族在肿瘤细胞和他们的激活，通过药理学干预，以优化抗癌治疗方式。本文是题为“凋亡：四十年后”的特刊的一部分。
Emergence of castration-resistant metastatic prostate cancer is due to activation of survival pathways, including apoptosis suppression and anoikis resistance, and increased neovascularization. Thus targeting of apoptotic players is of critical significance in prostate cancer therapy since loss of apoptosis and resistance to anoikis are critical in aberrant malignant growth, metastasis and conferring therapeutic failure. The majority of therapeutic agents act through intrinsic mitochondrial, extrinsic death receptor pathways or endoplasmic reticulum stress pathways to induce apoptosis. Current therapeutic strategies target restoring regulatory molecules that govern the pro-survival pathways such as PTEN which regulates AKT activity. Other strategies focus on reactivating the apoptotic pathways either by down-regulating anti-apoptotic players such as BCL-2 or by up-regulating pro-apoptotic protein families, most notably, the caspases. Caspases are a family of cystine proteases which serve critical roles in apoptotic and inflammatory signaling pathways. During tumorigenesis, significant loss or inactivation of lead members in the caspase family leads to impairing apoptosis induction, causing a dramatic imbalance in the growth dynamics, ultimately resulting in aberrant growth of human cancers. Recent exploitation of apoptosis pathways towards re-instating apoptosis induction via caspase re-activation has provided new molecular platforms for the development of therapeutic strategies effective against advanced prostate cancer as well as other solid tumors. This review will discuss the current cellular landscape featuring the caspase family in tumor cells and their activation via pharmacologic intervention towards optimized anti-cancer therapeutic modalities. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".