Mechanistic target of rapamycin (mTOR) is a protein kinase that regulates cellular growth, development, survival, and metabolism through integration of diverse extracellular and intracellular stimuli. Additionally, mTOR is involved in interplay of signalling pathways that regulate apoptosis and autophagy. In cells, mTOR is assembled into two complexes, mTORC1 and mTORC2. While mTORC1 is regulated by energy consumption, protein intake, mechanical stimuli, and growth factors, mTORC2 is regulated by insulin-like growth factor-1 receptor (IGF-1R), and epidermal growth factor receptor (EGFR). mTOR signalling pathways are considered the hallmark in cancer due to their dysregulation in approximately 70% of cancers. Through downstream regulators, ribosomal protein S6 kinase β-1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), mTORC1 influences various anabolic and catabolic processes in the cell. In recent years, several mTOR inhibitors have been developed with the aim of treating different cancers. In this review, we will explore the current developments in the mTOR signalling pathway and its importance for being targeted by various inhibitors in anti-cancer therapeutics.

The global incidence of breast cancer has significantly increased, highlighting the need for novel therapeutic strategies. Current treatment options are often limited by drug resistance and adverse effects, necessitating the exploration of alternative compounds. Naringenin, a naturally occurring flavonoid in citrus fruits, exhibits antimicrobial, anti‐atherogenic, hepatoprotective, anti‐inflammatory, and anticancer properties. This study evaluates the potential of naringenin as an inhibitor of breast cancer cell proliferation. MCF‐7 breast cancer cells were used as a model system to assess the anti‐proliferative effects of naringenin. Cell viability was evaluated using MTT and colony formation assays, while cell migration was analysed via wound healing assay. Flow cytometry and western blotting were performed to examine cell cycle arrest and apoptosis, and autophagy was assessed through western blotting and confocal microscopy. Naringenin inhibited cellular proliferation in a dose‐dependent manner by arresting cells in the S‐phase of the cell cycle. It significantly reduced cellular migration and increased early and late apoptosis. Autophagy induction was confirmed by elevated LC3‐II expression, p62 degradation, and LC3‐II–LAMP1 co‐localization. Additionally, C‐PARP expression was reduced when cells were co‐treated with naringenin and 3‐methyladenine (3‐MA), indicating pro‐apoptotic autophagy. This study demonstrates the anti‐migratory and anti‐proliferative effects of naringenin and its ability to induce pro‐apoptotic autophagy in human breast cancer cells, suggesting its potential as a therapeutic agent.

The canonical function of the Mdm2 oncoprotein is widely recognized as the negative regulation of the p53 tumor suppressor. However, growing evidence indicates that its physiological activities extend far beyond p53. Here, we show that Mdm2 promotes cell cycle progression at the G2/M phase through the ubiquitin-mediated degradation of the substrate recognition adaptor Cdt2 of the CRL4 ^Cdt2 E3 ubiquitin ligase complex, independently of p53. The attenuation of CRL4 ^Cdt2 activity by Mdm2 stabilizes its cell cycle-specific substrates including p21, Set8, and Cdt1, at the G2/M phase following their proteasomal degradation in the S phase. Furthermore, the delay in cell cycle progression at the G2/M phase and the decreased cell proliferation observed in the absence of Mdm2 are largely caused by an increase in Cdt2 and a subsequent decrease in p21. Collectively, our data illustrate a previously unexplored mechanism by which Mdm2 regulates the cell cycle and promotes cellular proliferation by neutralising the CR4 ^Cdt2 E3 ubiquitin ligase activity and subsequently stabilizing p21.