Genome-wide gene expression profile analyses using a
cDNA microarray containing 27,648 genes or expressed sequence tags identified MMS22L (
methyl methanesulfonate-sensitivity
protein 22-like) to be overexpressed in the majority of clinical lung and
esophageal cancers, but not expressed in normal organs except testis. Transfection of siRNAs against MMS22L into
cancer cells suppressed its expression and inhibited cell growth, while exogenous expression of MMS22L enhanced the growth of mammalian cells. MMS22L
protein was translocated to the nucleus and stabilized by binding to C-terminal portion of NFKBIL2 [nuclear factor of kappa (NFKB) light
polypeptide gene enhancer in B-cells inhibitor-like 2]. Expression of a C-terminal portion of NFKBIL2
protein including the MMS22L-interacting site in
cancer cells could reduce the levels of MMS22L in nucleus and suppressed
cancer cell growth. Interestingly, reduction of MMS22L by siRNAs in
cancer cells inhibited the TNF-α-dependent activation of RelA/p65 in the NFKB pathway and expression of its downstream anti-apoptotic molecules such as Bcl-XL and
TRAF1. In addition, knockdown of MMS22L expression also enhanced the apoptosis of
cancer cells that were exposed to
DNA-damaging agents including
5-FU and CDDP. Our data strongly suggest that targeting MMS22L as well as its interaction with NFKBIL2 could be a promising strategy for novel
cancer treatments, and also improve the efficacy of
DNA damaging anticancer drugs.