Plasmodium Infection Suppresses Colon Cancer Growth by Inhibiting Proliferation and Promoting Apoptosis Associated with Disrupting Mitochondrial Biogenesis and Mitophagy in Mice

Abstract

Background: Colon cancer is a common gastrointestinal tumor with a poor prognosis, which makes it urgent to explore new therapeutic strategies. The anti-tumor effect of Plasmodium infection has been reported in some murine models, but it is not clear whether it has an anti-colon cancer effect. In this study, we investigated the anti-colon cancer effect of Plasmodium infection and its related mechanisms using a mouse model of colon cancer.Methods: An experimental model was established by intraperitoneal injection of Plasmodium yoelii-infected erythrocytes into mice with colon cancer. The size of tumors was observed dynamically in mice, and the expression of Ki67 detected by immunohistochemistry was to analyze tumor cells proliferation. Apoptosis was assessed by Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) staining, and the expression of apoptosis concerned proteins, including Bax, Bcl-2, Caspase-9, Cleaved Caspase-3, were detected by western blot and immunohistochemistry, respectively. Transmission electron microscopy (TEM) was used to observe the ultrastructural change of colon cancer cells. And the expression of mitochondrial biogenesis correlative central protein, PGC-1α, and mitophagy relevant crucial proteins, PINK1/Parkin, were detected by western blot. Results: We found that Plasmodium infection reduced the weights and sizes of tumors and decreased the expression of Ki67 in colon cancer-bearing mice. Furthermore, Plasmodium infection promoted mitochondria-mediated apoptosis in colon cancer cells, as evidenced by the increased proportion of TUNEL-positive cells, the up-regulated expression of Bax, Caspase-9, and Cleaved Caspase-3 proteins, and the down-regulated expression of Bcl-2 protein. In colon cancer cells, we found destroyed nucleus, swollen mitochondria, missing cristae, and the decreased number of autolysosomes. In addition, Plasmodium infection disturbed mitochondrial biogenesis and mitophagy through the reduced expression of PGC-1α, PINK1, and Parkin proteins in colon cancer tissues.Conclusions: Plasmodium infection can play an anti-colon cancer role in mice by inhibiting proliferation and promoting mitochondria-mediated apoptosis in colon cancer cells, which may relate to mitochondrial biogenesis and mitophagy.