Modulating p-AMPK/mTOR Pathway of Mitochondrial Dysfunction Caused by MTERF1 Abnormal Expression in Colorectal Cancer Cells

Abstract

Human mitochondrial transcription termination factor 1 (MTERF1) has been demonstrated to play an important role in mitochondrial gene expression regulation. However, the molecular mechanism of MTERF1 in colorectal cancer (CRC) remains largely unknown. Here, we found that MTERF1 expression was significantly increased in colon cancer tissues compared with normal colorectal tissue by Western blotting, immunohistochemistry, and tissue microarrays (TMA). Overexpression of MTERF1 in the HT29 cell promoted cell proliferation, migration, invasion, and xenograft tumor formation, whereas knockdown of MTERF1 in HCT116 cells appeared to be the opposite phenotype to HT29 cells. Furthermore, MTERF1 can increase mitochondrial DNA (mtDNA) replication, transcription, and protein synthesis in colorectal cancer cells; increase ATP levels, the mitochondrial crista density, mitochondrial membrane potential, and oxygen consumption rate (OCR); and reduce the ROS production in colorectal cancer cells, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS) activity. Mechanistically, we revealed that MTERF1 regulates the AMPK/mTOR signaling pathway in cancerous cell lines, and we also confirmed the involvement of the AMPK/mTOR signaling pathway in both xenograft tumor tissues and colorectal cancer tissues. In summary, our data reveal an oncogenic role of MTERF1 in CRC progression, indicating that MTERF1 may represent a new therapeutic target in the future.

Metformin and thymoquinone co‐treatment enhance 5‐fluorouracil cytotoxicity by suppressing the PI3K/mTOR/HIF1α pathway and increasing oxidative stress in colon cancer cells

“…11,41 Moreover, cancer cells hyperactivate the PI3K/AKT/mTOR pathway by suppressing its endogenous inhibitors, PTEN and AMPKα, which subsequently inhibits PDH and stimulates LDHA enzymes by increasing the production of HIF1α. [13][14][15][16] Collectively, our results suggest that cancer cells could initially increase their antioxidant capacity to resist 5-FU-induced apoptosis, 8,9 whereas metabolic reprograming mechanisms underlying chemoresistance could require prolonged exposure to the cytotoxic drug. 11,15,16,41 However, more studies using different doses of 5-FU and/or longer durations of treatment are needed to validate our hypothesis.…”

“…[10][11][12] Other mechanisms underlying chemoresistance to 5-FU also include hyperstimulation of phosphatidylinositol-3-kinase (PI3K) located at the cell membrane, which subsequently activates mammalian target of rapamycin (mTOR) via protein kinase B (AKT). 13,14 Cancer cells also hyperactivate the PI3K/AKT/ mTOR oncogenic pathway by suppressing its natural inhibitors, phosphatase and tensin homolog (PTEN) and 5 0 adenosine monophosphate-activated protein kinase-α (AMPKα). [13][14][15][16] Sustained abnormal stimulation of the PI3K/AKT/mTOR network then upregulates hypoxia inducing factor-1α (HIF1α), which promotes fermentative glycolysis by concomitantly hyperactivating LDHA and downregulating PDH enzymes.…”

“…13,14 Cancer cells also hyperactivate the PI3K/AKT/ mTOR oncogenic pathway by suppressing its natural inhibitors, phosphatase and tensin homolog (PTEN) and 5 0 adenosine monophosphate-activated protein kinase-α (AMPKα). [13][14][15][16] Sustained abnormal stimulation of the PI3K/AKT/mTOR network then upregulates hypoxia inducing factor-1α (HIF1α), which promotes fermentative glycolysis by concomitantly hyperactivating LDHA and downregulating PDH enzymes. [13][14][15][16] In recent years, many studies have reported efficient tumoricidal activities for several non-chemotherapeutic agents against CRC by inducing cell cycle arrest and apoptosis, attenuating the PI3K/mTOR/HIF1α network, alongside promoting ROS production and oxidative glycolysis.…”

“…[13][14][15][16] Sustained abnormal stimulation of the PI3K/AKT/mTOR network then upregulates hypoxia inducing factor-1α (HIF1α), which promotes fermentative glycolysis by concomitantly hyperactivating LDHA and downregulating PDH enzymes. [13][14][15][16] In recent years, many studies have reported efficient tumoricidal activities for several non-chemotherapeutic agents against CRC by inducing cell cycle arrest and apoptosis, attenuating the PI3K/mTOR/HIF1α network, alongside promoting ROS production and oxidative glycolysis. In this context, the oral hypoglycaemic drug, metformin, exhibited potent anti-cancer effects against CRC by inhibiting cell cycle, downregulating the PI3K/mTOR/ HIF1α pathway, and promoting glucose oxidation with ROS-induced apoptosis.…”

“…Metabolic shifting from glucose oxidation to fermentation is another mechanism by which malignant cells impede their chemosensitivity to 5‐FU, and it involves hyperactivation of the lactate dehydrogenase‐A (LDHA) enzyme, alongside inhibition of pyruvate dehydrogenase (PDH) enzyme by upregulating its kinases (PDHKs) 10–12 . Other mechanisms underlying chemoresistance to 5‐FU also include hyperstimulation of phosphatidylinositol‐3‐kinase (PI3K) located at the cell membrane, which subsequently activates mammalian target of rapamycin (mTOR) via protein kinase B (AKT) 13,14 . Cancer cells also hyperactivate the PI3K/AKT/mTOR oncogenic pathway by suppressing its natural inhibitors, phosphatase and tensin homolog (PTEN) and 5′ adenosine monophosphate‐activated protein kinase‐α (AMPKα) 13–16 .…”