Claudins are integral
tight junction proteins that are responsible for maintaining the integrity of epithelial cell architecture and cell polarity.
Claudin-3 and -4 are overexpressed in several
cancers and have been shown to act as receptors for the
Clostridium perfringens enterotoxin (CPE), a toxin that causes rapid cell lysis. CPE has demonstrated effectiveness in treating several different
cancers in mouse models, provided that these
cancers express
claudin-3 or
claudin-4. Here, we show that
claudin-3/4 expression is not an absolute requirement for CPE action and, through overexpression and knockdown experiments, we identify
claudin-6 as a novel functional receptor for CPE. Indeed, UCI-101, an
ovarian cancer cell line highly sensitive to CPE, does not express
claudin-3/4 and knockdown of
claudin-6 in these cells decreases CPE sensitivity. Moreover, two different ovarian cell lines that are resistant to the effects of CPE can be made sensitive through
claudin-6 overexpression. Binding assays show that CPE can indeed bind
claudin-6 in cells and that this binding is associated with CPE cytotoxicity. Multicellular
tumor spheroids experiments demonstrate that
claudin-6 can also be a target of CPE in three-dimensional cultures. Our data establish
claudin-6 as a novel receptor for CPE and introduces the possibility of a novel targeted therapeutic for ovarian and other
cancers that express
claudin-6.