Anticancer drugs are effective against
tumors that depend on the molecular target of the
drug. Known targets of cytotoxic anticancer drugs are involved in cell proliferation; drugs acting on such targets are ineffective against nonproliferating
tumor cells, survival of which leads to eventual
therapy failure. Function-based genomic screening identified the
coatomer protein complex ζ1 (COPZ1) gene as essential for different
tumor cell types but not for normal cells. COPZ1 encodes a subunit of
coatomer protein complex 1 (
COPI) involved in intracellular traffic and autophagy. The knockdown of COPZ1, but not of COPZ2 encoding
isoform coatomer protein complex ζ2, caused Golgi apparatus collapse, blocked autophagy, and induced apoptosis in both proliferating and nondividing
tumor cells. In contrast, inhibition of normal cell growth required simultaneous knockdown of both COPZ1 and COPZ2. COPZ2 (but not COPZ1) was down-regulated in the majority of tumor cell lines and in clinical samples of different
cancer types. Reexpression of COPZ2 protected
tumor cells from killing by COPZ1 knockdown, indicating that
tumor cell dependence on COPZ1 is the result of COPZ2 silencing. COPZ2 displays no
tumor-suppressive activities, but it harbors
microRNA 152, which is silenced in
tumor cells concurrently with COPZ2 and acts as a
tumor suppressor in vitro and in vivo. Silencing of
microRNA 152 in different
cancers and the ensuing down-regulation of its host gene COPZ2 offer a therapeutic opportunity for proliferation-independent selective killing of
tumor cells by COPZ1-targeting agents.