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.

Cheng F ，Huang H ，Yin S ，Liu JS ，Sun P ... -  《Cell Death & Disease》

Overexpressed Gαi1 exerts pro-tumorigenic activity in nasopharyngeal carcinoma.

Yin DP ，Zhang H ，Teng H ，Zhang D ，Chen P ，Xie L ，Liu JS ... -  《Cell Death & Disease》

Targeting the mitochondrial protein YME1L to inhibit osteosarcoma cell growth in vitro and in vivo.

Exploring novel diagnostic and therapeutic biomarkers is extremely important for osteosarcoma. YME1 Like 1 ATPase (YME1L), locating in the mitochondrial inner membrane, is key in regulating mitochondrial plasticity and metabolic activity. Its expression and potential functions in osteosarcoma are studied in the present study. We show that YME1L mRNA and protein expression is significantly elevated in osteosarcoma tissues derived from different human patients. Moreover, its expression is upregulated in various primary and immortalized osteosarcoma cells. The Cancer Genome Atlas database results revealed that YME1L overexpression was correlated with poor overall survival and poor disease-specific survival in sarcoma patients. In primary and immortalized osteosarcoma cells, silencing of YME1L through lentiviral shRNA robustly inhibited cell viability, proliferation, and migration. Moreover, cell cycle arrest and apoptosis were detected in YME1L-silenced osteosarcoma cells. YME1L silencing impaired mitochondrial functions in osteosarcoma cells, causing mitochondrial depolarization, oxidative injury, lipid peroxidation and DNA damage as well as mitochondrial respiratory chain complex I activity inhibition and ATP depletion. Contrarily, forced YME1L overexpression exerted pro-cancerous activity and strengthened primary osteosarcoma cell proliferation and migration. YME1L is important for Akt-S6K activation in osteosarcoma cells. Phosphorylation of Akt and S6K was inhibited after YME1L silencing in primary osteosarcoma cells, but was strengthened with YME1L overexpression. Restoring Akt-mTOR activation by S473D constitutively active Akt1 mitigated YME1L shRNA-induced anti-osteosarcoma cell activity. Lastly, intratumoral injection of YME1L shRNA adeno-associated virus inhibited subcutaneous osteosarcoma xenograft growth in nude mice. YME1L depletion, mitochondrial dysfunction, oxidative injury, Akt-S6K inactivation, and apoptosis were detected in YME1L shRNA-treated osteosarcoma xenografts. Together, overexpressed YME1L promotes osteosarcoma cell growth, possibly by maintaining mitochondrial function and Akt-mTOR activation.

Sun X ，Shi C ，Dai J ，Zhang MQ ，Pei DS ，Yang L ... -  《-》

The mitochondrial protein YME1 Like 1 is important for non-small cell lung cancer cell growth.

The expression and biological function of the mitochondrial inner membrane protease YME1L (YME1 Like 1 ATPase) in NSCLC are tested here. Bioinformatical analyses and results from local human tissues show that YME1L expression is elevated in NSCLC tissues. YME1L upregulation was observed in primary and immortalized NSCLC cells. In NSCLC cells, shRNA-mediated silence of YME1L or dCas9/sgRNA-induced knockout (KO) of YME1L robustly suppressed cell growth and migration, and provoking apoptosis. YME1L shRNA/KO resulted in mitochondrial dysfunctions in NSCLC cells, leading to mitochondrial depolarization, ROS accumulation and ATP depletion. Conversely, ectopic YME1L overexpression augmented NSCLC cell proliferation and motility. Akt-S6K1 phosphorylation was reduced after YME1L shRNA/KO in primary NSCLC cells, but augmented after YME1L overexpression. Importantly, YME1L KO-caused anti-NSCLC cell activity was attenuated by a constitutively-activate Akt1 (S473D) construct. In vivo, subcutaneous NSCLC xenograft growth was remarkably slowed following intratumoral YME1L shRNA AAV injection in nude mice. YME1L knockdown, Akt-mTOR inactivation and ATP reduction were detected in YME1L-silenced NSCLC xenografts. Taken together, overexpressed YME1L in NSCLC exerts pro-tumorigenic function.

Xia Y ，He C ，Hu Z ，Wu Z ，Hui Y ，Liu YY ，Mu C ，Zha J ... -  《-》

Targeting nasopharyngeal carcinoma by artesunate through inhibiting Akt/mTOR and inducing oxidative stress.

Drug repurposing has become an alternative therapeutic strategy for cancer treatment given the known pharmacokinetics and toxicity. The inhibitory effects of artesunate have been reported in various cancers. In this work, we investigated the effects of artesunate in nasopharyngeal carcinoma (NPC). We demonstrate that artesunate significantly inhibits proliferation via arresting NPC cells at G2/M phase. It also induces apoptosis through caspase-dependent and mitochondria-independent pathways in multiple NPC cell lines. The combination of artesunate and cisplatin is synergistic in targeting NPC cells in in vitro cellular culture system and in vivo xenograft tumor models. Artesunate inhibits phosphorylation of essential molecules involved in Akt/mTOR pathway in NPC cells, such as Akt, mTOR, and 4EBP1, and its inhibitory effects are partially abolished by overexpression of constitutively active Akt. In addition, artesunate also induces mitochondrial dysfunction and oxidative stress via inhibiting mitochondrial respiration, increasing levels of mitochondrial superoxide and cellular reactive oxygen species (ROS), leading to decreased ATP levels. Two ROS scavengers partially abolish the inhibitory effects of artesunate in NPC cells. These data suggest that both inhibition of Akt/mTOR pathway and induction of ROS are required for the action of artesunate in NPC cells. Our work demonstrates that artesunate is a potential candidate for NPC treatment. Our work also highlights the critical roles of Akt/mTOR pathway and mitochondrial function in NPC cells.

Li Q ，Ni W ，Deng Z ，Liu M ，She L ，Xie Q ... -  《-》