ADAM12 promotes temozolomide resistance in glioblastoma by activating the TNF-α - NF-κB pathway.

Development of temozolomide (TMZ) resistance is a critical factor contributing to a poor prognosis in glioma patients. TMZ resistance is also closely associated with the phosphorylation level of NF-κB, yet targeted inhibition of NF-κB activity in glioma can be leveraged to overcome TMZ resistance. ADAM12, a protein significantly overexpressed in glioma cells, is implicated in the pathogenesis and progression of glioma, yet its role in the development of TMZ resistance is completely understood. We found that knockdown of ADAM12 was shown to arrest the glioma cell cycle, enhance apoptosis, inhibit DNA damage repair mechanisms, and sensitize glioma cells to TMZ. Targeting ADAM12 in vivo was found to increase the sensitivity of glioma cells to TMZ. Survival analysis indicated that ADAM12 serves as a prognostic marker for TMZ treatment. Using ELISA and protein interaction predictions via docking simulation, we identified the TNF-α shedding function of ADAM12 as a critical regulator of glioma progression. Furthermore, in glioma cell lines with unmethylated MGMT, the knockdown of ADAM12 enhanced sensitivity to TMZ by inhibiting the TNF-α/NF-κB pathway and reducing MGMT expression. In all, these results demonstrated that ADAM12 aids in shedding of membrane-bound TNF-a to drive TMZ resistance in glioma.