Selectively releasing resistance to TRAIL-mediated apoptosis in cancer cells as therapeutic option for hepatocellular carcinoma

TRAIL是一种肿瘤坏死因子相关的凋亡诱导配体，具有选择性地诱导肿瘤细胞凋亡而不损伤正常细胞的作用，因此被开发为一种有前景的癌症治疗方法。然而，有两个问题可能限制了TRAIL的临床应用：(1)在特定的病理条件下，TRAIL给药也可能导致正常细胞死亡；(2)某些类型的癌细胞对TRAIL的低反应性。在我们以前的工作中，我们已经实施了三种方法，可以通过靶向众所周知的致癌途径JNK、Src和β-catenin信号来提高试验的有效性和安全性。我们发现，抑制JNK和Src对TRAIL有明显的增敏作用，但对未转化的原代肝细胞无明显影响。这样，即使在对TRAIL敏感的正常肝细胞中，有效的抗肿瘤TRAIL浓度也可以降低到毒性可以忽略不计的水平。我们发现，β-连环蛋白通过促进TRAIL的可溶性诱饵受体骨保护素(OPG)的表达，在结肠癌中发挥显著的抗细胞凋亡作用。抑制JNK和Src还导致细胞周期停滞，取消锚定非依赖性生长，降低癌细胞的侵袭性。这些发现证实了TRAIL是一种很有前途的癌症治疗方法，JNK、Src和OPG是肿瘤治疗的候选靶点。在未来的实验中，我们将致力于研究这些途径如何决定对凋亡的抵抗，评估癌细胞对TRAIL的差异增敏机制，并将转移我们的体外研究。

TRAIL, the TNF-related apoptosis inducing ligand is known for selectively inducing apoptosis in cancer cells while leaving normal cells unharmed and is thus being developed as a promising cancer therapy. However, two issues potentially limiting its clinical applicability have to be addressed: (1) the possibility that TRAIL administration also causes cell death in normal cells under specific pathological conditions and (2) the low response of certain types of cancer cells to TRAIL. In our previous works we have implemented three approaches which could improve TRAIL effectiveness and safety by targeting the well known carcinogenetic pathways of JNK, Src and beta-catenin signalling. We found that inhibition of JNK and Src greatly sensitized liver cancer cell lines but not primary non transformed hepatocytes to TRAIL. This, in a way that effective antitumor TRAIL concentrations could be reduced to levels with negligible toxicity even in normal hepatocytes sensitized to TRAIL. We found that beta-catenin exerts a remarkable antiapoptotic effect in colon carcinoma by driving the expression of osteoprotegerin (OPG) which acts as a soluble decoy receptor for TRAIL. JNK and Src inhibition also caused cell cycle arrest, abolished anchorage independent growth and reduced invasive properties of cancer cells. These findings confirm that the administration of TRAIL is a promising approach to cancer therapy and candidates JNK, Src and OPG as targets for the therapy of tumors. In future experiments we shall aim at investigating how these pathways determine resistance to apoptosis, at assessing the mechanisms of differential sensitization of cancer cells to TRAIL, and will transfer our in vitro studies in vivo.