The Anti‐Proliferative Effect of Doxorubicin is Catalyzed through the Proteolytic Activation of CREB3L1

Abstract

Doxorubicin is an extensively used chemotherapy agent, but the drug response rate is low owing to an unclear mechanism of action. Here we report that the anti‐proliferative effect of doxorubicin is dependent upon the proteolytic activation of CREB3L1. CREB3L1 is synthesized as a membrane‐bound precursor. The N‐terminal domain of CREB3L1 projects into the cytosol and can function as a transcription factor. Doxorubicin stimulates the proteolytic cleavage of CREB3L1 to release the N‐terminal domain from the membrane so that it can enter the nucleus to transcribe anti‐proliferative genes. TM4SF20, a polytopic transmembrane protein, plays an important role in the regulation of CREB3L1 proteolytic activation. Under normal conditions, TM4SF20 prevents the proteolytic activation of CREB3L1 precursor. Doxorubicin activates CREB3L1 cleavage by inducing the de novo synthesis of ceramide. The accumulation of ceramide reverses the membrane topology of TM4SF20 by preventing the N‐terminal peptide of TM4SF20 from functioning as a signal sequence. The topology reversal of TM4SF20 leads to the proteolytic activation of CREB3L1. These findings are clinically significant as only cancer cells expressing CREB3L1 are sensitive to doxorubicin both in vitro and in vivo. Our data suggests that CREB3L1 may be used as a biomarker to predict the effectiveness of doxorubicin‐based therapy.Sources of Research Support: National Institutes of Health (AI‐090119, HL‐20948, and AI 70116‐6)