FBXW7 regulates MAP7 through ubiquitination to affect the phenotypic characteristics and paclitaxel sensitivity of paclitaxel-resistant lung adenocarcinoma cells.

BACKGROUND: The emergence of resistance to paclitaxel (PTX) poses a major challenge to the effective treatment of lung adenocarcinoma (LUAD). This study aimed to elucidate the role of microtubule-associated protein 7 (MAP7) in regulating cell phenotypes and PTX sensitivity of PTX-resistant LUAD cells.

METHODS: Two PTX-resistant LUAD cell lines (A549/PTX and HCC-827/PTX) were generated. The effects on cell apoptosis, migration, invasiveness, tube formation, colony formation, and proliferation were evaluated. Subcutaneous xenograft studies were conducted to assess the in vivo role. The regulatory mechanism of F-Box and WD repeat domain containing 7 (FBXW7) on MAP7 protein was examined through stability analysis and immunoprecipitation (IP) assay.

RESULTS: In PTX-resistant LUAD tumors and cell lines, MAP7 expression was elevated (P < 0.001), while FBXW7 expression was reduced (P < 0.001). Depletion of MAP7 hindered the colony formation (P = 0.0001 or P = 0.0005), invasiveness (P = 0.0004 or P = 0.0005), and migratory capacity (P = 0.0004 or P = 0.001) of A549/PTX and HCC-827/PTX cells. Furthermore, MAP7 overexpression attenuated the anti-cancer effects of PTX in subcutaneous xenograft models (P = 0.0081 or P < 0.001). Mechanistically, FBXW7 destabilized MAP7 protein stability (P < 0.001) by promoting its polyubiquitination at K48. Knockdown of FBXW7 enhanced cell colony formation (P = 0.0029 or P = 0.0007), invasiveness (P = 0.0005 or P < 0.0001), and migration (P = 0.0002 or P < 0.0001) of A549/PTX and HCC-827/PTX cells. Re-expression of MAP7 counteracted (P < 0.01) the inhibitory effects of elevated FBXW7 expression on these cellular processes. In addition, the FBXW7-MAP7 cascade was shown to regulate tube formation in human umbilical vein endothelial cells (HUVECs) (P < 0.01).

CONCLUSIONS: Our findings indicate that the FBXW7-MAP7 axis plays a critical role in regulating the malignant phenotypes and PTX sensitivity of PTX-resistant LUAD cell lines, suggesting a potential therapeutic strategy to improve the efficacy of PTX-based therapies in LUAD.