The BRCT Domain from the Homologue of the Oncogene PES1 in Leishmania major (LmjPES) Promotes Malignancy and Drug Resistance in Mammalian Cells

Abstract

Around 15% of cancer cases are attributable to infectious agents. Epidemiological studies suggest that an association between leishmaniasis and cancer does exist. Recently, the homologue of PES1 in Leishmania major (LmjPES) was described to be involved in parasite infectivity. Mammalian PES1 protein has been implicated in cellular processes like cell cycle regulation. Its BRCT domain has been identified as a key factor in DNA damage-responsive checkpoints. This work aimed to elucidate the hypothetical oncogenic implication of BRCT domain from LmjPES in host cells. We generated a lentivirus carrying this BRCT domain sequence (lentiBRCT) and a lentivirus expressing the luciferase protein (lentiLuc), as control. Then, HEK293T and NIH/3T3 mammalian cells were infected with these lentiviruses. We observed that the expression of BRCT domain from LmjPES conferred to mammal cells in vitro a greater replication rate and higher survival. In in vivo experiments, we observed faster tumor growth in mice inoculated with lentiBRCT respect to lentiLuc HEK293T infected cells. Moreover, the lentiBRCT infected cells were less sensitive to the genotoxic drugs. Accordingly, gene expression profiling analysis revealed that BRCT domain from LmjPES protein altered the expression of proliferation- (DTX3L, CPA4, BHLHE41, BMP2, DHRS2, S100A1 and PARP9), survival- (BMP2 and CARD9) and chemoresistance-related genes (DPYD, Dok3, DTX3L, PARP9 and DHRS2). Altogether, our results reinforced the idea that in eukaryotes, horizontal gene transfer might be also achieved by parasitism like Leishmania infection driving therefore to some crucial biological changes such as proliferation and drug resistance.

BRCT Domains: Structure, Functions, and Implications in Disease—New Therapeutic Targets for Innovative Drug Discovery against Infections

“…In vivo experiments in athymic nude mice revealed a significant capability of those transgenic cells to generate highly proliferative tumours. This study reinforced the existing link between parasitism and cancer development through potential horizontal gene transfer [ 83 ]. In addition, it shed some light on the relevance of BRCT domains in parasites.…”

“…Recently, BRCT from LmjPES was expressed in mammalian cells. These transgenic mammalian cells expressing the BRCT domain from Leishmania parasites dramatically increased their growth rate and their resistance to DNA-damaging treatments such as etoposide and 5-fluorouracil [ 83 ]. In addition, those cells exhibited altered expressions of mitochondrial, proliferation, and chemoresistance genes.…”