Gold Nanoparticles Disrupt the IGFBP2/mTOR/PTEN Axis to Inhibit Ovarian Cancer Growth

Abstract

By exploiting the self‐therapeutic properties of gold nanoparticles (GNPs) a molecular axis that promotes the growth of high‐grade serous ovarian cancer (HGSOC), one of the deadliest gynecologic malignancies with poorly understood underlying molecular mechanisms, has been identified. The biodistribution and toxicity of GNPs administered by intravenous or intraperitoneal injection, both as a single dose or by repeated dosing over two weeks are first assessed; no biochemical or histological toxicity to vital organs is found. Using an orthotopic patient‐derived xenograft (PDX) model of HGSOC, the authors then show that GNP treatment robustly inhibits tumor growth. Investigating the molecular mechanisms underlying the GNP efficacy reveals that GNPs downregulate insulin growth factor binding protein 2 (IGFBP2) by disrupting its autoregulation via the IGFBP2/mTOR/PTEN axis. This mechanism is validated by treating a cell line‐based human xenograft tumor with GNPs and an mTOR dual‐kinase inhibitor (PI‐103), either individually or in combination with GNPs; GNP and PI‐103 combination therapy inhibit ovarian tumor growth similarly to GNPs alone. This report illustrates how the self‐therapeutic properties of GNPs can be exploited as a discovery tool to identify a critical signaling axis responsible for poor prognosis in ovarian cancer and provides an opportunity to interrogate the axis to improve patient outcomes.

Comprehensive Pan-Cancer Analyses of Immunogenic Cell Death as a Biomarker in Predicting Prognosis and Therapeutic Response

“…We found that IGF2BP3 could regulate the expression of key DAMP-related genes. Besides, we found that expression of IGFBP2 negatively correlated with OS in PCPG patients, which was consistent with previous studies which also identified IGFBP2 as an oncogene in various tumor types [ 95 , 96 , 97 ]. Altogether, these indicated that insulin-like growth factor binding protein family played an important role in the ICD tumor process.…”

Gold Nanoparticles Inhibit Macropinocytosis by Decreasing KRAS Activation

“…injection (100–300 μg per mouse) in either an acute setting (24 h and single injection of GNP) or a chronic setting (GNP injections every 2 days for 14 days). Importantly, biochemical and immunohistochemical analyses revealed the absence of toxicity . In the present study, three doses of GNP treatment did not appreciably reduce the tumor size.…”

“…Cell proliferation was measured by cell counting by the trypan blue method as described previously . Nearly 60–80% inhibition of proliferation in all the cancer cell lines tested was seen following GNP treatment when compared with nontreated controls (Figure c).…”

“…The ability of GNP to inhibit HB-GFs has shown promise to inhibit tumor growth, metastasis, and therapy resistance in a number of cancers. ,, GNP have also been used as a therapeutic molecule in a number of noncancerous diseases including rheumatoid arthritis, diseases of the eye, and neurodegenerative diseases such as Alzheimer’s disease. − However, the ability of GNP to modulate KRAS activation and macropinocytosis has not yet been tested. Our finding of GNP-mediated inhibition of macropinocytosis and tumor growth in two independent preclinical models of PDAC demonstrates its potential utility to inhibit tumor growth in other malignancies harboring RAS mutations.…”

“…Cell proliferation was measured by cell counting by the trypan blue method as described previously. 23 Nearly 60−80% inhibition of proliferation in all the cancer cell lines tested was seen following GNP treatment when compared with nontreated controls (Figure 2c). All of the results taken together suggest that GNP treatment inhibits macropinocytosis and cancer cell proliferation by decreasing RAS activation and RAS signaling cascades.…”