Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are among the most common cancers across the world. Particularly, a large number of patients with CRC also have liver metastasis. Currently, there are just a few targeted drugs against these two kinds of tumors which can only benefit a very small population of patients. Therefore, the need of more effective therapeutic drugs or strategies for these two types of cancers is urgent. PS341 (Bortezomib) is the first proteasome inhibitor drug which has been approved in clinical treatment for multiple myeloma. Here we demonstrated that PS341 negatively regulated HCC and CRC both in vitro and in vivo, including the inhibition of cell proliferation, epithelial-mesenchymal transition (EMT), the expression of stemness-related genes, cell migration and invasiveness. Mechanically, PS341 upregulated the expression of FOXO3, which inhibited the transcriptional activation of CTNNB1. The downregualtion of CTNNB1 led to apoptosis, cell cycle arrest, and the inhibition of migration, invasion, self-renewal and tumor formation of these two cancer types. In sum, our findings shed light on the PS341 mediated targeted therapy against both HCC and CRC in the future.

中文翻译：

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PS341通过FOXO3 / CTNNB1信号通路抑制肝细胞和结直肠癌细胞。

肝细胞癌（HCC）和结直肠癌（CRC）是世界上最常见的癌症。特别地，大量CRC患者也有肝转移。当前，针对这两种肿瘤的靶向药物很少，只能使一小部分患者受益。因此，迫切需要针对这两种类型的癌症的更有效的治疗药物或策略。PS341（硼替佐米）是首个蛋白酶体抑制剂药物，已被批准用于多发性骨髓瘤的临床治疗。在这里，我们证明了PS341在体内和体外均负调控HCC和CRC，包括抑制细胞增殖，上皮-间质转化（EMT），干性相关基因的表达，细胞迁移和侵袭性。机械上，PS341上调FOXO3的表达，从而抑制CTNNB1的转录激活。CTNNB1的下调导致这两种癌症类型的凋亡，细胞周期停滞以及迁移，侵袭，自我更新和肿瘤形成的抑制。总而言之，我们的发现为将来PS341介导的针对HCC和CRC的靶向治疗提供了启示。