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, and thus new therapeutic strategies are urgently needed. The antitumor 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 17XNL-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 used to analyze tumor cell proliferation. Apoptosis was assessed by terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining, and the expression of apoptosis-related proteins including Bax, Bcl-2, caspase-9, and cleaved caspase-3 was detected by western blot and immunohistochemistry, respectively. Transmission electron microscopy (TEM) was used to observe the ultrastructural change in 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 weight and size 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 upregulated expression of Bax, caspase-9, and cleaved caspase-3 proteins, and the downregulated expression of Bcl-2 protein. In colon cancer cells, we found destroyed cell nuclei, swollen mitochondria, missing cristae, and a 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 cells. 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. Graphical Abstract

A novel enemy of cancer: recent investigations into protozoan anti-tumor properties

“…Intraperitoneally injected Plasmodium has been shown to reduce MMP9 production by inhibiting IGF-1 signaling through the accumulation of hemozoin, thus inhibiting tumor angiogenesis in vivo ( Wang et al., 2020 ). In addition, tumor cells from Plasmodium -infected mice exhibited increased expression of Bax, caspase-9, and cleaved caspase-3 proteins, while Bcl-2 expression was decreased, resulting in the promotion of mitochondria-mediated apoptosis ( Yao et al., 2022 ). Unfortunately, the specific pathways regulating these non-immune mechanisms following Plasmodium infection remain unclear, necessitating further molecular studies to elucidate the mechanisms involved.…”

New 1,2,3-Triazole-Coumarin-Glycoside Hybrids and Their 1,2,4-Triazolyl Thioglycoside Analogs Targeting Mitochondria Apoptotic Pathway: Synthesis, Anticancer Activity and Docking Simulation

“…There are numerous studies that have shown that there is a close link between mitochondria and cancer development [ 2 ]. As mitochondria play a key role in cell proliferation and death, many studies have demonstrated that targeting mitochondria can inhibit tumor growth or induce apoptosis [ 3 ]. Targeted chemotherapy involves several approaches, including selective enzyme inhibition, which has been recognized as an attractive strategy for inhibiting tumour growth [ 4 , 5 , 6 , 7 ].…”