Light‐Controlled Cell‐Cycle Arrest and Apoptosis

• Published in: Angewandte Chemie Vol. 133; no. 3; pp. 1207 - 1216
• Main Authors: Uhl, Edgar, Wolff, Friederike, Mangal, Sriyash, Dube, Henry, Zanin, Esther
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 18-01-2021
• Subjects: Aldehydes; Apoptosis; Biocompatibility; Biological activity; Biological effects; Cancer; Cell cycle; chemical biology; Chemistry; In vivo methods and tests; Irradiation; Light irradiation; Metaphase; MG132; photopharmacology; proteasome; Proteasome inhibitors; Radiation
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202008267

Cell‐cycle interference by small molecules has widely been used to study fundamental biological mechanisms and to treat a great variety of diseases, most notably cancer. However, at present only limited possibilities exist for spatio‐temporal control of the cell cycle. Here we report on a photocaging strategy to reversibly arrest the cell cycle at metaphase or induce apoptosis using blue‐light irradiation. The versatile proteasome inhibitor MG132 is photocaged directly at the reactive aldehyde function effectively masking its biological activity. Upon irradiation reversible cell‐cycle arrest in the metaphase is demonstrated to take place in vivo. Similarly, apoptosis can efficiently be induced by irradiation of human cancer cells. With the developed photopharmacological approach spatio‐temporal control of the cell cycle is thus enabled with very high modulation, as caged MG132 shows no effect on proliferation in the dark. In addition, full compatibility of photo‐controlled uncaging with dynamic microscopy techniques in vivo is demonstrated. This visible‐light responsive tool should be of great value for biological as well as medicinal approaches in need of high‐precision targeting of the proteasome and thereby the cell cycle and apoptosis.
Blue‐light control of the proteasome is achieved using a new photocaging approach. Photolabile protection of the versatile proteasome inhibitor MG132 at the reactive aldehyde function abolished proteasome binding. After irradiation MG132 activity is restored resulting in cell‐cycle arrest at metaphase or apoptosis. This visible‐light‐responsive tool opens up new avenues for spatiotemporal control of the proteasome in basic and medicinal research.