Is IGFBP-2 a novel-link between DNA-damage, metabolism, and cancer?

Abstract

Prostate cancer (PC) is the second most common cancer in men in the UK. The insulinlike growth factor-binding protein (IGFBP) family is composed of 6 proteins (1-6). IGFBP-2 is the second most abundant IGFBP in circulation after IGFBP-3. IGFBP-2 is involved in many biological activities such as cell proliferation, invasion, and migration. IGFBP-2 increases the half-life of the insulin-like growth factors (IGFs) by protecting them from proteolysis. IGFBP-2 exhibits both IGF-dependent and IGF-independent activity. Hyperglycaemia has been shown to decrease the effectiveness of chemotherapy in PC
cells, an effect mediated by IGFBP-2. Although treatments are available for PC, patients often develop resistance to such therapy. Understanding the resistance mechanisms will improve the treatments by identifying the key molecules that could be targeted, such as IGFBP-2.
Previous studies have shown that DNA double-strand breaks (DSBs) induced in the S phase of the cell cycle are repaired by the nonhomologous end-joining (NHEJ) DNA repair
mechanism, by its major component, DNA-dependent protein kinase (DNA-PK). In this investigation, exposing PC cells to etoposide (ETO) caused DNA DSBs. As a result, the NHEJ DNA repair mechanism was activated by autophosphorylation of the DNA-PK catalytic subunit (DNAPKcs) to repair the DSBs. We have also shown an increase in IGFBP-2 protein and mRNA in response to ETO. These observations suggested that IGFBP-2 is involved in the NHEJ DNA repair mechanism, which we confirmed by silencing IGFBP-2, which produced more DNA DSBs than cells treated with ETO only.
IGFBP-2 was observed in the nucleus, where it interacted with DNA-PK during the formation of DNA DSBs and enhanced DNA repair. Dosing cells with chemotherapy after silencing IGFBP-2 resulted in increased DNA DSBs and a decrease in DNA repair by DNAPKcs and hyperglycaemia-induced IGFBP-2 expression, inhibited the ability of etoposide to induce DNA damage. Together, these data suggest that IGFBP-2 plays an important role in the DNA repair mechanism of prostate cancer cells and could provide opportunities for optimising current treatment regimens.

Date of Award	24 Jan 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Kalina Biernacka (Supervisor), Jeffrey Holly (Supervisor) & Claire M Perks (Supervisor)