Kras突变亚型对结肠癌细胞对FL118（一种survivin、Mcl-1、XIAP、cIAP2和MdmX的新型抑制剂）的敏感性有明显影响。

Kras mutation subtypes distinctly affect colorectal cancer cell sensitivity to FL118, a novel inhibitor of survivin, Mcl-1, XIAP, cIAP2 and MdmX.

作者信息

Thangaiyan Rabi, Aljahdali Ieman Am, Lent-Moore Kelsey Y, Liao Jianqun, Ling Xiang, Li Fengzhi

机构信息

Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center Buffalo, New York 14263, USA.

Department of Cellular & Molecular Biology, Roswell Park Comprehensive Cancer Center Buffalo, New York 14263, USA.

出版信息

Am J Transl Res. 2021 Jul 15;13(7):7458-7474. eCollection 2021.

PMID:34377229

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8340187/

Abstract

Mutation-activated Kras in cancer cells is a well-known challenging treatment-resistant factor that plays a critical role in treatment resistance. Human colorectal cancer (CRC) has four major Kras mutations; Kras (34.2%), Kras (21%), Kras (20%) and Kras (8.4%). Here, we report that while FL118 (a novel inhibitor of survivin, Mcl-1, XIAP, cIAP2 and MdmX) exhibits high efficacy to kill CRC cells and eliminate CRC tumors, CRC cells/tumors with different Kras mutation subtypes in the defined p53/APC genetic statuses exhibit different sensitivity to FL118 treatment. Using CRC cell lines, SW620 (Kras, mutant p53, mutant APC), DLD-1 (Kras, wild type p53, mutant APC) and SNU-C2B (Kras, mutant p53, wild type APC), we demonstrated that silencing of Kras and Kras using Kras-specific shRNA significantly increased CRC cell IC, while silencing of Kras decreased the CRC cell IC. This finding suggests that both Kras and Kras are required for showing higher FL118 efficacy, while the presence of Kras could somehow decrease FL118 efficacy under the defined p53/APC genetic status. Consistent with this notion, silencing of Kras in SW620 cells decreased FL118-induced apoptosis, while silencing of Kras in DLD-1 cells increased the FL118-induced apoptosis. Furthermore, forced expression of Kras in SW620 cells increased FL118-induced apoptosis, while forced expression of Kras in DLD-1 cells decreased FL118-induced apoptosis. Additionally, FL118 induced differential reactive oxygen species (ROS) production in SW620, DLD-1 and SNU-C2B cells. Our studies in animal models further confirmed that SW620 tumors are the most sensitive tumor to FL118 treatment; SNU-C2B tumors are the second most sensitive tumor to FL118 treatment; and the DLD-1 tumors are the least sensitive tumor. These findings would be useful for predicting FL118 sensitivity to patients' CRC tumors with the defined Kras mutation subtypes under the defined p53/APC genetic status.

摘要

癌细胞中突变激活的Kras是一个众所周知的具有挑战性的治疗抗性因子，在治疗抗性中起关键作用。人类结直肠癌（CRC）有四种主要的Kras突变；Kras（34.2%）、Kras（21%）、Kras（20%）和Kras（8.4%）。在此，我们报告，虽然FL118（一种survivin、Mcl-1、XIAP、cIAP2和MdmX的新型抑制剂）在杀死CRC细胞和消除CRC肿瘤方面表现出高效能，但在定义的p53/APC基因状态下，具有不同Kras突变亚型的CRC细胞/肿瘤对FL118治疗表现出不同的敏感性。使用CRC细胞系SW620（Kras、突变型p53、突变型APC）、DLD-1（Kras、野生型p53、突变型APC）和SNU-C2B（Kras、突变型p53、野生型APC），我们证明使用Kras特异性shRNA沉默Kras和Kras可显著增加CRC细胞IC，而沉默Kras则降低CRC细胞IC。这一发现表明，Kras和Kras对于显示更高的FL118效能都是必需的，而在定义的p53/APC基因状态下，Kras的存在可能会以某种方式降低FL118效能。与此观点一致，在SW620细胞中沉默Kras可降低FL118诱导的细胞凋亡，而在DLD-1细胞中沉默Kras则增加FL118诱导的细胞凋亡。此外，在SW620细胞中强制表达Kras可增加FL118诱导的细胞凋亡，而在DLD-1细胞中强制表达Kras则降低FL118诱导的细胞凋亡。此外，FL118在SW620、DLD-1和SNU-C2B细胞中诱导了不同的活性氧（ROS）产生。我们在动物模型中的研究进一步证实，SW620肿瘤是对FL118治疗最敏感的肿瘤；SNU-C2B肿瘤是对FL118治疗第二敏感的肿瘤；而DLD-1肿瘤是最不敏感的肿瘤。这些发现将有助于预测在定义的p53/APC基因状态下，具有定义的Kras突变亚型的患者CRC肿瘤对FL118的敏感性。