Restoration of A2M reduces drug resistance and malignancy in paclitaxel-resistant lung cancer cells

The development of acquired paclitaxel resistance poses a significant challenge in managing lung cancer clinically. Understanding the mechanism and developing effective strategies to counter paclitaxel resistance are highly desired. To explore the potential mechanisms of acquired paclitaxel resistance, we established a series of lung cancer cell lines exhibiting different levels of resistance to paclitaxel. Transcriptomic RNA-sequencing revealed a progressive decrease in alpha-2-macroglobulin (A2M) levels as paclitaxel resistance advanced in NCI-H446 cells. This was accompanied by the upregulation of known paclitaxel resistance inducers ABCB1, TMEM243, and ID1. A2M loss was further validated in paclitaxel-resistant A549 and HCC827 lung cancer cells. TCGA and CPTAC analyses demonstrated that A2M is downregulated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), inversely correlating with tumor progression. Restoring A2M expression inhibited proliferation and invasion in paclitaxel-resistant lung cancer cells, suggesting its tumor-suppressing role in lung cancer. Notably, restoring A2M re-suppressed the expression of the paclitaxel resistance mediators (ABCB1, TMEM243 and ID1) in the drug-resistant cells, and re-sensitized them to paclitaxel. In summary, our data indicate that A2M is progressively lost during the development of paclitaxel resistance in lung cancer, and restoring A2M may help overcome this resistance. Thus, A2M deficiency may serve as both a predictor and a therapeutic target for paclitaxel resistance in lung cancer.