Expression and functional implications of YME1L in nasopharyngeal carcinoma.

Mitochondria play a crucial role in the progression of nasopharyngeal carcinoma (NPC). YME1L, a member of the AAA ATPase family, is a key regulator of mitochondrial function and has been implicated in various cellular processes and diseases. This study investigates the expression and functional significance of YME1L in NPC. YME1L exhibits significant upregulation in NPC tissues from patients and across various primary human NPC cells, while its expression remains relatively low in adjacent normal tissues and primary nasal epithelial cells. Employing genetic silencing through the shRNA strategy or knockout (KO) via the CRISPR-sgRNA method, we demonstrated that YME1L depletion disrupted mitochondrial function, leading to mitochondrial depolarization, reactive oxygen species (ROS) generation, lipid peroxidation, and ATP reduction within primary NPC cells. Additionally, YME1L silencing or KO substantially impeded cell viability, proliferation, cell cycle progression, and migratory capabilities, concomitant with an augmentation of Caspase-apoptosis activation in primary NPC cells. Conversely, ectopic YME1L expression conferred pro-tumorigenic attributes, enhancing ATP production and bolstering NPC cell proliferation and migration. Moreover, our findings illuminate the pivotal role of YME1L in Akt-mTOR activation within NPC cells, with Akt-S6K phosphorylation exhibiting a significant decline upon YME1L depletion but enhancement upon YME1L overexpression. In YME1L-silenced primary NPC cells, the introduction of a constitutively-active Akt1 mutant (caAkt1, at S473D) restored Akt-S6K phosphorylation, effectively ameliorating the inhibitory effects imposed by YME1L shRNA. In vivo studies revealed that intratumoral administration of YME1L-shRNA-expressing adeno-associated virus (AAV) curtailed subcutaneous NPC xenograft growth in nude mice. Furthermore, YME1L downregulation, concurrent with mitochondrial dysfunction and ATP reduction, oxidative injury, Akt-mTOR inactivation, and apoptosis induction were evident within YME1L-silenced NPC xenograft tissues. Collectively, these findings shed light on the notable pro-tumorigenic role by overexpressed YME1L in NPC, with a plausible mechanism involving the promotion of Akt-mTOR activation.

Synergistic Phototherapy-Molecular Targeted Therapy Combined with Tumor Exosome Nanoparticles for Oral Squamous Cell Carcinoma Treatment.

Oral squamous cell carcinoma (OSCC) contributes to more than 90% of all oral malignancies, yet the performance of traditional treatments is impeded by limited therapeutic effects and substantial side effects. In this work, we report a combinational treatment strategy based on tumor exosome-based nanoparticles co-formulating a photosensitizer (Indocyanine green) and a tyrosine kinase inhibitor (Gefitinib) (IG@EXOs) for boosting antitumor efficiency against OSCC through synergistic phototherapy-molecular targeted therapy. The IG@EXOs generate distinct photothermal/photodynamic effects through enhanced photothermal conversion efficiency and ROS generation, respectively. In vivo, the IG@EXOs efficiently accumulate in the tumor and penetrate deeply to the center of the tumor due to passive and homologous targeting. The phototherapy effects of IG@EXOs not only directly induce potent cancer cell damage but also promote the release and cytoplasmic translocation of Gefitinib for achieving significant inhibition of cell proliferation and tumor angiogenesis, eventually resulting in efficient tumor ablation and lymphatic metastasis inhibition through the synergistic phototherapy-molecular targeted therapy. We envision that the encouraging performances of IG@EXOs against cancer pave a new avenue for their future application in clinical OSCC treatment.