Stress granules affect the dual PI3K/mTOR inhibitor response by regulating the mitochondrial unfolded protein response.

Drug resistance remains a challenge in ovarian cancer. In addition to aberrant activation of relevant signaling pathways, the adaptive stress response is emerging as a new spotlight of drug resistance in cancer cells. Stress granules (SGs) are one of the most important features of the adaptive stress response, and there is increasing evidence that SGs promote drug resistance in cancer cells. In the present study, we compared two types of ovarian cancer cells, A2780 and SKOV3, using the dual PI3K/mTOR inhibitor, PKI-402. We found that SGs were formed and SGs could intercept the signaling factor ATF5 and regulate the mitochondrial unfolded protein response (UPRmt) in A2780 cells. Therefore, exploring the network formed between SGs and membrane-bound organelles, such as mitochondria, which may provide a new insight into the mechanisms of antitumor drug functions.

RNA binding protein: coordinated expression between the nuclear and mitochondrial genomes in tumors.

Mitochondria are the only organelles regulated by two genomes. The coordinated translation of nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), which together co-encode the subunits of the oxidative phosphorylation (OXPHOS) complex, is critical for determining the metabolic plasticity of tumor cells. RNA-binding protein (RBP) is a post-transcriptional regulatory factor that plays a pivotal role in determining the fate of mRNA. RBP rapidly and effectively reshapes the mitochondrial proteome in response to intracellular and extracellular stressors, mediating the cytoplasmic and mitochondrial translation balance to adjust mitochondrial respiratory capacity and provide energy for tumor cells to adapt to different environmental pressures and growth needs. This review highlights the ability of RBPs to use liquid-liquid phase separation (LLPS) as a platform for translation regulation, integrating nuclear-mitochondrial positive and retrograde signals to coordinate cross-department translation, reshape mitochondrial energy metabolism, and promote the development and survival of tumor cells.

The IL-33/ST2 axis affects tumor growth by regulating mitophagy in macrophages and reprogramming their polarization.

Objective: Macrophages are a major component of the tumor microenvironment. M1 macrophages secrete pro-inflammatory factors that inhibit tumor growth and development, whereas tumor-associated macrophages (TAMs) mainly exhibit an M2 phenotype. Our previous studies have shown that the interleukin-33/ST2 (IL-33/ST2) axis is essential for activation of the M1 phenotype. This study investigates the role of the IL-33/ST2 axis in TAMs, its effects on tumor growth, and whether it participates in the mutual conversion between the M1 and M2 phenotypes. Methods: Bone marrow-derived macrophages were extracted from wildtype, ST2 knockout (ST2-/-), and Il33-overexpressing mice and differentiated with IL-4. The mitochondrial and lysosomal number and location, and the expression of related proteins were used to analyze mitophagy. Oxygen consumption rates and glucose and lactate levels were measured to reveal metabolic changes. Results: The IL-33/ST2 axis was demonstrated to play an important role in the metabolic conversion of macrophages from OXPHOS to glycolysis by altering mitophagy levels. The IL-33/ST2 axis promoted enhanced cell oxidative phosphorylation, thereby further increasing M2 polarization gene expression and ultimately promoting tumor growth (P < 0.05) (Figure 4). This metabolic shift was not due to mitochondrial damage, because the mitochondrial membrane potential was not significantly altered by IL-4 stimulation or ST2 knockout; however, it might be associated with the mTOR activity. Conclusions: These results clarify the interaction between the IL-33/ST2 pathway and macrophage polarization, and may pave the way to the development of new cancer immunotherapies targeting the IL-33/ST2 axis.

PGC1α regulates mitochondrial oxidative phosphorylation involved in cisplatin resistance in ovarian cancer cells via nucleo-mitochondrial transcriptional feedback.

Mitochondria play an important role in effective cell energy production and cell survival under stress conditions, such as treatment with chemotherapeutic drugs. Mitochondrial biogenesis is increased in ovarian cancer tissues, which is accompanied by alteration of mitochondrial energy metabolism, structure, and dynamics. These factors are involved in tumorigenesis and apoptosis resistance, highlighting the role of mitochondria in resisting cisplatin toxicity. Cisplatin-resistant ovarian cancer cells are dependent on mitochondrial OXPHOS for energy supply, and intracellular PGC1α-mediated mitochondrial biogenesis levels are increased in this cell line, indicating the important role of mitochondrial oxidative phosphorylation in cisplatin resistance. As PGC1α is a key molecule for integrating and coordinating nuclear DNA and mitochondrial DNA transcriptional machinery, an investigation into the regulatory mechanism PGC1α in mitochondrial energy metabolism via transcription may provide new clues for solving chemotherapy resistance. In the present study, it was demonstrated that inhibiting the expression of PGC1α decreased nuclear and mitochondrial DNA transcription factor expression, leading to increased lactic acid production and decreased cellular oxygen consumption and mitochondrial oxidative phosphorylation. Furthermore, mitochondrial stress-induced ROS production, as a feedback signal from mitochondria to the cell nucleus, increased PGC1α expression in SKOV3/DDP cells, which was involved in mitochondrial oxidative phosphorylation regulation. Collectively, the present study provides evidence that PGC1α-mediated nuclear and mitochondrial transcription feedback regulates energy metabolism and is involved in ovarian cancer cells escaping apoptosis during cisplatin treatment.

Hypoxia-induced NAD+ interventions promote tumor survival and metastasis by regulating mitochondrial dynamics.

Hypoxia, an important feature of the tumor microenvironment, is responsible for the chemo-resistance and metastasis of malignant solid tumors. Recent studies indicated that mitochondria undergo morphological transitions as an adaptive response to maintain self-stability and connectivity under hypoxic conditions. NAD+ may not only provide reducing equivalents for biosynthetic reactions and in determining energy production, but also functions as a signaling molecule in mitochondrial dynamics regulation. In this review, we describe the upregulated KDAC deacetylase expression in the mitochondria and cytoplasm of tumor cells that results from sensing the changes in NAD+ to control mitochondrial dynamics and distribution, which is responsible for survival and metastasis in hypoxia.

Inhibition of pyruvate dehydrogenase kinase­1 by dicoumarol enhances the sensitivity of hepatocellular carcinoma cells to oxaliplatin via metabolic reprogramming.

The Warburg effect is a unique metabolic feature of the majority of tumor cells and is closely related to chemotherapeutic resistance. Pyruvate dehydrogenase kinase 1 (PDK1) is considered a 'switch' that controls the fate of pyruvate in glucose metabolism. However, to date, to the best of our knowledge, there are only a few studies to available which had studied the reduction of chemotherapeutic resistance via the metabolic reprogramming of tumor cells with PDK1 as a target. In the present study, it was found dicoumarol (DIC) reduced the phosphorylation of pyruvate dehydrogenase (PDH) by inhibiting the activity of PDK1, which converted the metabolism of human hepatocellular carcinoma (HCC) cells to oxidative phosphorylation, leading to an increase in mitochondrial reactive oxygen species ROS (mtROS) and a decrease in mitochondrial membrane potential (MMP), thereby increasing the apoptosis induced by oxaliplatin (OXA). Furthermore, the present study elucidated that the targeting of PDK1 may be a potential strategy for targeting metabolism in the chemotherapy of HCC. In addition, DIC as an 'old drug' exhibits novel efficacy, bringing new hope for antitumor therapy.