Bombesin-drug conjugates in targeted therapy for small cell lung cancer.

Small cell lung cancer (SCLC) is a aggressive form of primary lung neoplasm that often presents in elderly smokers. While stage I SCLC can be managed with surgery, extensive-stage disease is managed with chemotherapy using etoposide and cisplatin among other agents, and often complemented by radiation therapy to the chest and cranium. Recent advances in pharmacological research have yielded novel antibody and peptide-conjugated adjunctive chemotherapy, of which bombesin and bombesin receptors have played an important role due to their overexpression in SCLC and other lung cancers.

CGI-58/ABHD5 is phosphorylated on Ser239 by protein kinase A: control of subcellular localization.

CGI-58/ABHD5 coactivates adipose triglyceride lipase (ATGL). In adipocytes, CGI-58 binds to perilipin 1A on lipid droplets under basal conditions, preventing interaction with ATGL. Upon activation of protein kinase A (PKA), perilipin 1A is phosphorylated and CGI-58 rapidly disperses into the cytoplasm, enabling lipase coactivation.

Comparative gene identification 58/α/β hydrolase domain 5 lacks lysophosphatidic acid acyltransferase activity.

Mutations in the gene encoding comparative gene identification 58 (CGI-58)/α/β hydrolase domain 5 (ABHD5) cause Chanarin-Dorfman syndrome, characterized by excessive triacylglycerol storage in cells and tissues. CGI-58 has been identified as a coactivator of adipose TG lipase (ATGL) and a lysophosphatidic acid acyltransferase (LPAAT). We developed a molecular model of CGI-58 structure and then mutated predicted active site residues and performed LPAAT activity assays of recombinant WT and mutated CGI-58.