Tang Michelle J, Tai Isabella T
Division of Gastroenterology, University of British Columbia, 2775 Laurel Street, Vancouver, British Columbia, Canada.
J Biol Chem. 2007 Nov 23;282(47):34457-67. doi: 10.1074/jbc.M704459200. Epub 2007 Sep 26.
Chemotherapy resistance accounts for the high mortality rates in patients with advanced cancers. We previously used a genomics approach to determine novel genes associated with this phenomenon and identified secreted protein acidic and rich in cysteine (SPARC) as a chemosensitizer capable of reversing therapy resistance in colorectal cancer cells by enhancing apoptosis in vitro and tumor regression in vivo. Here, we examined the mechanisms by which SPARC enhances apoptosis in the presence of chemotherapy. We show that SPARC potentiates apoptosis by augmenting the signaling cascade in a caspase-8-dependent manner, because apoptosis can be abolished by caspase 8 small interfering RNA in the presence of SPARC. This occurs independently of death receptor activation and leads to downstream involvement of Bid and subsequent apoptosis. Interestingly, this results from an interaction between SPARC and the N terminus of the procaspase-8 DED-containing domain. These exciting findings provide an initial map of the apoptosis signaling events mediated by SPARC and how this can ultimately result in the reversal of chemotherapy resistance and enhanced tumor regression. This signaling cascade can be exploited therapeutically and may have potential clinical implications for patients with advanced and therapy-refractory cancers.
化疗耐药是晚期癌症患者高死亡率的原因。我们之前采用基因组学方法来确定与这一现象相关的新基因，并鉴定出富含半胱氨酸的酸性分泌蛋白（SPARC）是一种化学增敏剂，它能够通过在体外增强细胞凋亡以及在体内促进肿瘤消退来逆转结肠癌细胞的治疗耐药性。在此，我们研究了SPARC在化疗存在的情况下增强细胞凋亡的机制。我们发现，SPARC通过以半胱天冬酶-8依赖的方式增强信号级联反应来增强细胞凋亡，因为在存在SPARC的情况下，半胱天冬酶8小干扰RNA可消除细胞凋亡。这一过程独立于死亡受体激活，并导致Bid的下游参与及随后的细胞凋亡。有趣的是，这是由SPARC与含死亡效应结构域的半胱天冬酶-8原酶N端之间的相互作用引起的。这些令人兴奋的发现提供了由SPARC介导的细胞凋亡信号事件的初步图谱，以及这如何最终导致化疗耐药性的逆转和肿瘤消退的增强。这种信号级联反应可用于治疗，可能对晚期和难治性癌症患者具有潜在的临床意义。
