Exploring dual effects of dinutuximab beta on cell death and proliferation of insulinoma

Abstract

Insulinoma INS‐1 cells are pancreatic beta cell tumors. Dinutuximab beta (DB) is a monoclonal antibody used in the treatment of neuroblastoma. The aim of this study is to investigate the effects of DB on pancreatic beta cell tumors at the molecular level. DB (Qarziba®) was available from EUSA Pharma. Streptozotocin (STZ) was used induce to cell cytotoxicity. DB was applied to the cells before or after the STZ application. KCND3, KCNN4, KCNK1, and PTHrP gene expression levels were analyzed by q‐RT‐PCR, and protein levels were analyzed by Western blotting. Analysis of glucose‐stimulated insulin secretion was performed. Ca+2 and CA19‐9 levels were determined by the ELISA kit. PERK, CHOP, HSP90, p‐c‐Jun, p‐Atf2, and p‐Elk1 protein levels were analyzed by simple WES. Decreased KCND3, KCNK1, and PTHrP protein levels and increased KCND3, KCNN4, KCNK1, and PTHrP gene expression levels were observed with DB applied after STZ application. Cell dysfunction was detected with DB applied before and after STZ application. Ca19‐9 and Ca+2 levels were increased with DB applied after STZ application. PERK, CHOP, and p‐Elk1 levels decreased, while HSP90 levels increased with DB applied after STZ application. CHOP, p‐Akt‐2, and p‐c‐Jun levels increased in the DB group. As a result, INS‐1 cells go to cell death via the ERK signaling pathway without ER stress and release insulin with the decrease of K+ channels and an increase in Ca+2 levels with DB applied after STZ application. Moreover, the cells proliferate via JNK signaling with DB application. DB holds promise for the treatment of insulinoma. The study should be supported by in vivo studies.