Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
Mol Cancer. 2022 Apr 27;21(1):106. doi: 10.1186/s12943-022-01579-9.
Lung cancer is a kind of malignancy with high morbidity and mortality worldwide. Paclitaxel (PTX) is the main treatment for non-small cell lung cancer (NSCLC), and resistance to PTX seriously affects the survival of patients. However, the underlying mechanism and potential reversing strategy need to be further explored.
We identified ALDH2 as a PTX resistance-related gene using gene microarray analysis. Subsequently, a series of functional analysis in cell lines, patient samples and xenograft models were performed to explore the functional role, clinical significance and the aberrant regulation mechanism of ALDH2 in PTX resistance of NSCLC. Furthermore, the pharmacological agents targeting ALDH2 and epigenetic enzyme were used to investigate the diverse reversing strategy against PTX resistance.
Upregulation of ALDH2 expression is highly associated with resistance to PTX using in vitro and in vivo analyses of NSCLC cells along with clinicopathological analyses of NSCLC patients. ALDH2-overexpressing NSCLC cells exhibited significantly reduced PTX sensitivity and increased biological characteristics of malignancy in vitro and tumor growth and metastasis in vivo. EHMT2 (euchromatic histone lysine methyltransferase 2) inhibition and NFYA (nuclear transcription factor Y subunit alpha) overexpression had a cooperative effect on the regulation of ALDH2. Mechanistically, ALDH2 overexpression activated the RAS/RAF oncogenic pathway. NSCLC/PTX cells re-acquired sensitivity to PTX in vivo and in vitro when ALDH2 was inhibited by pharmacological agents, including the ALDH2 inhibitors Daidzin (DZN)/Disulfiram (DSF) and JIB04, which reverses the effect of EHMT2.
Our findings suggest that ALDH2 status can help predict patient response to PTX therapy and ALDH2 inhibition may be a promising strategy to overcome PTX resistance in the clinic.
肺癌是一种在全球范围内发病率和死亡率都很高的恶性肿瘤。紫杉醇（PTX）是治疗非小细胞肺癌（NSCLC）的主要药物，对 PTX 的耐药性严重影响患者的生存。然而，其潜在的机制和潜在的逆转策略仍需进一步探索。
我们使用基因微阵列分析鉴定出 ALDH2 是与 PTX 耐药相关的基因。随后，在细胞系、患者样本和异种移植模型中进行了一系列功能分析，以探讨 ALDH2 在 NSCLC 对 PTX 耐药中的功能作用、临床意义和异常调控机制。此外，还使用针对 ALDH2 和表观遗传酶的药理学药物来研究针对 PTX 耐药的不同逆转策略。
通过 NSCLC 细胞的体外和体内分析以及 NSCLC 患者的临床病理分析，发现 ALDH2 表达上调与 PTX 耐药高度相关。ALDH2 过表达的 NSCLC 细胞表现出明显降低的 PTX 敏感性和体外恶性生物学特性增加以及体内肿瘤生长和转移增加。EHMT2（ euchromatic histone lysine methyltransferase 2）抑制和 NFYA（nuclear transcription factor Y subunit alpha）过表达对 ALDH2 的调控具有协同作用。在机制上，ALDH2 过表达激活了 RAS/RAF 致癌通路。当 ALDH2 被药理学药物抑制时，包括 ALDH2 抑制剂 Daidzin（DZN）/Disulfiram（DSF）和 JIB04，NSCLC/PTX 细胞在体内和体外重新获得对 PTX 的敏感性，从而逆转了 EHMT2 的作用。
我们的研究结果表明，ALDH2 状态可以帮助预测患者对 PTX 治疗的反应，而 ALDH2 抑制可能是克服临床 PTX 耐药的一种有前途的策略。
