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  • Furthermore we also found that the basic level of ROS

    2024-02-22

    Furthermore, we also found that the basic level of ROS was markedly lower in mtDNA-reduced SW480 pretomanid than that in the parent cells. Endogenous ROS is most notably produced at the sites of complex I and complex III [5], it might be plausible that the decreased quantity of ROS observed in mtDNA-reduced cells mainly resulted from impaired functions of these two complexes lacking the subunits encoded by mtDNA. Resistance of tumor cells to chemotherapeutic agent-induced apoptosis is a major impediment in the treatment of many cancers. Previous researches indicate that low mtDNA copy number in tumors has been associated with worse prognosis in CRC [11,23]. In the present study, we observed that the cytotoxicity of both 5-Fu and oxaliplatin was obviously decreased in mtDNA-reduced SW480 cells. MtDNA-reduced SW480 cells were highly resistant to 5-Fu- and oxaliplatin-induced apoptosis. MtDNA content reduction might induce chemotherapy failure which resulted in progression of colorectal cancer. It is known that the Akt pathway promotes cell survival and proliferation through a series of downstream events, including the stimulation of aerobic glycolysis, the suppression of apoptosis, and the enhancement of nutrient uptake and energy metabolism through the activation of mTOR [34]. Moreover, mTOR activation also executes pro-survival and anti-apoptotic activities [40]. While upregulation of the PI3K/Akt pathway has been suggested as a possible mechanism leading to drug resistance in cancer cells [41,42], its role in mtDNA-reduced CRC is unknown. Our data indicated that mtDNA-reduced cells exhibited activation of the Akt/mTOR pathway compared with parent cells and this activation was decreased when the mtDNA content was restored. This activation of the Akt/mTOR survival pathway might protect mtDNA-reduced cells from drugs-induced apoptosis. The role of this signaling pathway was further evaluated using the PI3K/Akt inhibitor LY294002. Treatment with this inhibitor restored the susceptibility of mtDNA-reduced cells to drug-induced apoptosis. The Akt/mTOR pathway might be a potential therapeutic target for the mtDNA-reduced cells.
    Conflict of interests
    Acknowledgments This work was supported by the National Natural Science Foundation of China (grant number 81472798).
    Introduction Atherosclerosis, which can result in cardiovascular disease, is a leading cause of morbidity and mortality in industrialized countries (Wong, 2014). Atherosclerosis lesions characterized by a thin fibrous cap, large lipid core and abundant macrophage accumulation are referred to as “vulnerable plaques” (Rohwedder et al., 2012). These lesions are susceptible to rupture, leading to thrombosis and eventually to myocardial and cerebral infarction (Badimon and Vilahur, 2014). Apoptosis of lesional macrophages, along with their defective function in efferocytosis, is known to promote plaques necrosis, which leads to plaques instability and thrombosis (Tabas et al., 2009). Previous work has shown that macrophage autophagy plays a protective role in AS and that it functions as a promoter of cholesterol efflux, (Tabas, 2005; Schrijvers et al., 2007; Ouimet et al., 2011) suggesting that the mechanism underlying macrophage apoptosis and autophagy is important. Legumain, also referred to as asparaginyl endopeptidase (AEP), belongs to the C13 family of cysteine proteases. Legumain has been found to play important roles in kidney physiology, immunity, atherogenesis and bone metabolism (Clerin et al., 2008). Cancer cells that express high levels of AEP exhibit enhanced migratory and invasive capabilities via the activation of pro-MMP2 and cathepsins (Chen et al., 2001; Guo et al., 2013). Moreover, legumain is highly expressed in tumor-associated macrophages both in vitro and in vivo (Lin et al., 2013). In recent years, legumain expression has been observed in plaques, suggesting that it might participate in atherogenesis. Mattock et al. reported that unstable regions of plaques contain increased levels of active legumain. Legumain overexpression in macrophages alters intracellular processing of cathepsin-L to its mature 25 kDa form, suggesting that legumain could contribute to plaques instability (Mattock et al., 2010). However, the mechanism underlying the effect of legumain on plaques instability remains unknown.