METHOD: The cell viability, sphere-forming and xenografts assay were used to evaluate the ability of ASIV to reverse taxol-resistance. Immunohistochemistry, cytokine application, small-interfering RNA, small molecule inhibitors, and RNA-seq approaches were applied to characterize the molecular mechanism of inhibition of epiregulin (EREG) and downstream signaling by ASIV to reverse taxol-resistance.

RESULTS: ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes. Finally, it was observed that TGFβ and Hedgehog signaling were downstream of EREG/ErbB/ERK, which could be targeted using inhibitors to reverse the taxol resistance of NSCLC.