A2M restoration reduces drug resistance and malignant properties in paclitaxel-resistant lung cancer cells

Acquired paclitaxel resistance is a major challenge for lung cancer treatment in the clinic. Deciphering the mechanism and thereby developing effective strategies against paclitaxel resistance are highly desired. To explore the possible mechanism underlying acquired paclitaxel resistance, we established paclitaxel resistant lung cancer cell lines with different levels of paclitaxel resistance. Using transcriptomic RNA-sequencing, we identified that Alpha-2-Macroglobulin (A2M) was gradually decreased with the progression of paclitaxel resistance in NCI-H446 cells, along with concomitant upregulation of well-known paclitaxel resistance inducers ABCB1, TMEM243, and ID1. A2M loss was further validated in paclitaxel-resistant A549 and HCC827 lung cancer cell lines. TCGA and CPTAC analyses showed that A2M is downregulated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) cancers, negatively correlated with tumor progression. A2M restoration suppressed the proliferation and invasion in paclitaxel resistant lung cancer cells, suggesting an anti-tumorigenic role of A2M in lung cancer. Furthermore, A2M restoration obviously suppressed the expression of the paclitaxel resistance mediators ABCB1, TMEM243 and ID1, and re-sensitized the resistant cells to paclitaxel. Collectively, our data suggest that the stepwise loss of the anti-tumor A2M contributes to the development of paclitaxel resistance in lung cancer, and that restoring A2M may help to overcome the paclitaxel resistance probably by down-regulating ABCB1, TMEM243 and ID1.Therefore, A2M deficiency may serve as a predictor and therapeutic target for paclitaxel resistance in lung cancer.