Autophagic cell death or abortive autophagy has been proposed to eliminate damaged as well as
cancer cells, but there remains a critical gap in our knowledge in how this process is regulated. The goal of this study was to identify modulators of the autophagic cell death pathway and elucidate their effects on cellular signaling and function. The result of our
siRNA library screenings show that an intact coatomer complex I (
COPI) is obligatory for productive autophagy. Depletion of
COPI complex members decreased cell survival and impaired productive autophagy which preceded endoplasmic reticulum stress. Further, abortive autophagy provoked by
COPI depletion significantly altered
growth factor signaling in multiple
cancer cell lines. Finally, we show that
COPI complex members are overexpressed in an array of
cancer cell lines and several types of
cancer tissues as compared to normal cell lines or tissues. In
cancer tissues, overexpression of
COPI members is associated with poor prognosis. Our results demonstrate that the coatomer complex is essential for productive autophagy and cellular survival, and thus inhibition of
COPI members may promote cell death of
cancer cells when apoptosis is compromised.