Cancer cells gain drug resistance through a complex mechanism, in which nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) are critical contributors. Because NACHT, LRR and PYD domains-containing
protein (NLRP)
inflammasomes mediate IL-1β maturation and NF-κB activation, we investigated the role of
inflammasome sensor NLRP1 in acquired drug resistance to
temozolomide (TMZ) in
melanoma. The sensitivity of
melanoma cells to TMZ was negatively correlated with the expression levels of O6-methylguanine-DNA
methyltransferase (MGMT), the
enzyme to repair TMZ-induced DNA lesions. When MGMT-low human
melanoma cells (1205Lu and HS294T) were treated with TMZ for over two months, MGMT was upregulated, and cells became resistant. However, the resistance mechanism was independent of MGMT, and the cells that acquired TMZ resistance showed increased NLRP1 expression, NLRP
inflammasome activation, IL-1β secretion, and NF-κB activity, which contributed to the acquired resistance to TMZ. Finally, blocking
IL-1 receptor (IL-1R) signaling with IL-1R antagonist decreased TMZ-resistant 1205Lu
tumor growth in vivo. Although
inflammation has been associated with drug resistance in various
cancers, our paper is the first to demonstrate the involvement of NLRP in the development of acquired drug resistance. Because
drug-tolerant
cancer cells become cross-tolerant to other classes of
cancer drugs, NLRP1 might be a suitable therapeutic target in
drug-resistant
melanoma, as well as in other
cancers.