bims-stacyt 2023-08-06 papers

Cytokine Growth Factor Rev. 2023 Jul 29. pii: S1359-6101(23)00035-7. [Epub ahead of print]

Role of exosomes in transferring chemoresistance through modulation of cancer glycolytic cell metabolism.

Mahrou Vahabi, Annalisa Comandatore, Marika A Franczak, Ryszard T Smolenski, Godefridus J Peters, Luca Morelli, Elisa Giovannetti.

Chemoresistance constitute a major obstacle in cancer treatment, leading to limited options and decreased patient survival. Recent studies have revealed a novel mechanism of chemoresistance acquisition: the transfer of information via exosomes, small vesicles secreted by various cells. Exosomes play a crucial role in intercellular communication by carrying proteins, nucleic acids, and metabolites, influencing cancer cell behavior and response to treatment. One crucial mechanism of resistance is cancer metabolic reprogramming, which involves alterations in the cellular metabolic pathways to support the survival and proliferation of drug-resistant cancer cells. This metabolic reprogramming often includes increased glycolysis, providing cancer cells with the necessary energy and building blocks to evade the effects of chemotherapy. Notably, exosomes have been found to transport glycolytic enzymes, as identified in proteomic profiling, leading to the reprogramming of metabolic pathways, facilitating altered glucose metabolism and increased lactate production. As a result, they profoundly impact the tumor microenvironment, promoting tumor progression, survival, immune evasion, and drug resistance.Understanding the complexities of such exosome-mediated cell-to-cell communication might open new therapeutic avenues and facilitate biomarker development in managing cancers characterized by aggressive glycolytic features. Moreover, given the intricate nature of metabolic abnormalities combining future exosome-based-targeted therapies with existing treatments like chemotherapy, immunotherapy, and targeted therapies holds promise for achieving synergistic effects to overcome resistance and improve cancer treatment outcomes.

Keywords: Cancer metabolism; Cell-to-cell communication; Chemoresistance; Exosomes; Glycolysis

DOI: https://doi.org/10.1016/j.cytogfr.2023.07.004

Mol Cell. 2023 Jul 28. pii: S1097-2765(23)00526-9. [Epub ahead of print]

O-GlcNAcylation of Raptor transduces glucose signals to mTORC1.

Chenchen Xu, Xiaoqing Pan, Dong Wang, Yuanyuan Guan, Wenyu Yang, Xing Chen, Ying Liu.

The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient levels. Dysregulation of mTORC1 results in a broad spectrum of diseases. Glucose is the primary energy supply of cells, and therefore, glucose levels must be accurately conveyed to mTORC1 through highly responsive signaling mechanisms to control mTORC1 activity. Here, we report that glucose-induced mTORC1 activation is regulated by O-GlcNAcylation of Raptor, a core component of mTORC1, in HEK293T cells. Mechanistically, O-GlcNAcylation of Raptor at threonine 700 facilitates the interactions between Raptor and Rag GTPases and promotes the translocation of mTOR to the lysosomal surface, consequently activating mTORC1. In addition, we show that AMPK-mediated phosphorylation of Raptor suppresses Raptor O-GlcNAcylation and inhibits Raptor-Rags interactions. Our findings reveal an exquisitely controlled mechanism, which suggests how glucose coordinately regulates cellular anabolism and catabolism.

Keywords: O-GlcNAcylation; Raptor; glucose sensing; mTOR

DOI: https://doi.org/10.1016/j.molcel.2023.07.011

iScience. 2023 Aug 18. 26(8): 107370

Mitochondrial UQCC3 controls embryonic and tumor angiogenesis by regulating VEGF expression.

Guimin Zhang, Binrui Liu, Yun Yang, Shuo Xie, Lingcheng Chen, Hui Luo, Jian Zhong, Yinhao Wei, Fengzhu Guo, Jia Gan, Fan Zhu, Lin Xu, Qiqi Li, Yuge Shen, Huajin Zhang, Yan Liu, Rong Li, Hongxin Deng, Hanshuo Yang.

Mitochondria play important roles in angiogenesis. However, the mechanisms remain elusive. In this study, we found that mitochondrial ubiquinol-cytochrome c reductase complex assembly factor 3 (UQCC3) is a key regulator of angiogenesis. TALEN-mediated knockout of Uqcc3 in mice caused embryonic lethality at 9.5-10.5 days postcoitum, and vessel density was dramatically reduced. Similarly, knockout of uqcc3 in zebrafish induced lethality post-fertilization and impaired vascular development. Knockout of UQCC3 resulted in slower tumor growth and angiogenesis. Mechanistically, UQCC3 was upregulated under hypoxia, promoted reactive oxygen species (ROS) generation, enhanced HIF-1α stability and increased VEGF expression. Finally, higher expression of UQCC3 was associated with poor prognosis in multiple types tumors, implying a role for UQCC3 in tumor progression. In conclusion, our findings highlight the important contribution of UQCC3 to angiogenesis under both physiological and pathological conditions, indicating the potential of UQCC3 as a therapeutic target for cancer.

Keywords: Biological sciences; Cancer systems biology; Natural sciences; Systems biology

DOI: https://doi.org/10.1016/j.isci.2023.107370

J Biol Chem. 2023 Jul 29. pii: S0021-9258(23)02142-7. [Epub ahead of print] 105114

ER stress decreases exosome production through adiponectin/T-cadherin-dependent and -independent pathways.

Keita Fukuoka, Ryohei Mineo, Shunbun Kita, Shiro Fukuda, Tomonori Okita, Emi Kawada-Horitani, Masahito Iioka, Kohei Fujii, Keitaro Kawada, Yuya Fujishima, Hitoshi Nishizawa, Maeda Norikazu, Iichiro Shimomura.

Exosomes, extracellular vesicles (EVs) produced within cells, mediate both the disposal of intracellular waste and communication with distant cells, and they are involved in a variety of disease processes. Although disease modifications of exosome cargos have been well studied, it has been poorly investigated how disease processes, such as endoplasmic reticulum (ER) stress, affect EV production. We previously reported that adiponectin, an adipocyte-secreted salutary factor, increases systemic exosome levels through T-cadherin-mediated enhancement of exosome biogenesis. In the present study, we demonstrated that adiponectin/T-cadherin-dependent EV production was susceptible to ER stress and that low-dose tunicamycin significantly reduced EV production in the presence, but not in the absence, of adiponectin. Moreover, pharmacological or genetic activation of IRE1α, a central regulator of ER stress, downregulated T-cadherin at the mRNA and protein levels as well as attenuated EV production. In addition, adiponectin/T-cadherin-independent EV production was attenuated under ER stress conditions. Repeated administration of tunicamycin to mice decreased circulating small EVs without decreasing tissue T-cadherin expression. Mechanistically, IRE1α activation by silencing of the XBP1 transcription factor upregulated the canonical IFN pathway and decreased EV production. The IFN pathway, when it was activated by polyinosinic-polycytidylic acid [poly(I:C)], also significantly attenuated EV production. Thus, we concluded that ER stress decreases exosome production through adiponectin/T-cadherin-dependent and -independent pathways.

Keywords: Adiponectin; ER stress; Exosome; Extracellular vesicle; T-cadherin

DOI: https://doi.org/10.1016/j.jbc.2023.105114