Racial differences in the expression of inhibitors of apoptosis (IAP) proteins in extracellular vesicles (EV) from prostate cancer patients.

Salma Khan,Tino W Sanchez,Jennifer Simpson,Saied Mirshahidi,Amber Gonda,James C Lynch,David Turay,Nathan R Wall,Carlos A Casiano,Daotai Nie

doi:10.1371/journal.pone.0183122

Abstract

African-American men with prostate cancer typically develop more aggressive tumors than men from other racial/ethnic groups, resulting in a disproportionately high mortality from this malignancy. This study evaluated differences in the expression of inhibitors of apoptosis proteins (IAPs), a known family of oncoproteins, in blood-derived exosomal vesicles (EV) between African-American and European-American men with prostate cancer. The ExoQuick™ method was used to isolate EV from both plasma and sera of African-American (n = 41) and European-American (n = 31) men with prostate cancer, as well as from controls with no cancer diagnosis (n = 10). EV preparations were quantified by acetylcholinesterase activity assays, and assessed for their IAP content by Western blotting and densitometric analysis. Circulating levels of the IAP Survivin were evaluated by ELISA. We detected a significant increase in the levels of circulating Survivin in prostate cancer patients compared to controls (P<0.01), with the highest levels in African-American patients (P<0.01). African-American patients with prostate cancer also contained significantly higher amounts of EVs in their plasma (P<0.01) and sera (P<0.05) than European-American patients. In addition, EVs from African-American patients with prostate cancer contained significantly higher amounts of the IAPs Survivin (P<0.05), XIAP (P<0.001), and cIAP-2 (P<0.01) than EVs from European-American patients. There was no significant correlation between expression of IAPs and clinicopathological parameters in the two patient groups. Increased expression of IAPs in EVs from African-American patients with prostate cancer may influence tumor aggressiveness and contribute to the mortality disparity observed in this patient population. EVs could serve as reservoirs of novel biomarkers and therapeutic targets that may have clinical utility in reducing prostate cancer health disparities.

Highlights

African American (AA) men suffer from a disproportionately high incidence and mortality of prostate cancer (PCa) compared to European American (EA) men and men of other racial and ethnic backgrounds [1, 2]
We report for the first time significantly higher circulating levels of exosomal vesicles (EV) as well as exosomal inhibitors of apoptosis proteins (IAPs) in serum/ plasma from AA-PCa patients compared to EA-PCa patients and controls with no PCa diagnosis
In a previous proteomics study we reported that EV-derived proteins purified from PCa patients serum were differentially expressed in ethnically diverse populations, with sets of proteins that were unique to either AA or EA patients, as well as proteins that were common to both groups [30]

Summary

Introduction

African American (AA) men suffer from a disproportionately high incidence and mortality of prostate cancer (PCa) compared to European American (EA) men and men of other racial and ethnic backgrounds [1, 2]. In order to understand the molecular determinants contributing these disparities, it has become important to identify and characterize biomarkers of cancer development and biological factors that may contribute to the increased PCa mortality observed among AA men [4,5,6]. Extracellular vesicles (EVs) have been described originating from numerous cellular populations including cancers and reside stably in biofluids of patients [13]. They are highly heterogeneous, variable in size, and contain what is believed to be a snapshot of the cellular contents of their cell of origin in their lumen and definitive molecules giving the EV distinct molecular and functional characteristics on their membrane surfaces [14]. We and others have shown that the proteins residing both luminal and on the surfaces of EVs may facilitate uptake and function and in the case of cancer have been described to facilitate the aggressive phenotypes of cancer proliferation, invasion and therapeutic resistance to their recipient cells [14,15,16,17]

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