Aberrant LETM1 elevation dysregulates mitochondrial functions and energy metabolism and promotes lung metastasis in
Yulu Shi1, Quan Kang2, Hong Zhou1
1Stem Cell Biology and Therapy Laboratory, The Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China.
Abstract:
Osteosarcoma is a differentiation-deficient disease, and despite the unique advantages and great potential of differentiation therapy, there are only a few known differentiation inducers, and little research has been done on their targets. Cell differentiation is associated with an increase in mitochondrial content and activity. The metabolism of some tumor cells is characterized by impaired oxidative phosphorylation, as well as up-regulation of aerobic glycolysis and pentose phosphate pathways. Leucine-containing zipper and EF-hand transmembrane protein 1 (LETM1) is involved in the maintenance of mitochondrial morphology and is closely associated with tumorigenesis and progression, as well as cancer cell stemness. We found that MG63 and 143B osteosarcoma cells overexpress LETM1 and exhibit abnormalities in mitochondrial structure and function. Knockdown of LETM1 partially restored the mitochondrial structure and function, inhibited the pentose phosphate pathway, promoted oxidative phosphorylation, and led to osteogenic differentiation. It also inhibited spheroid cell formation, proliferation, migration, and invasion in an in vitro model. When LETM1 was knocked down in vivo, there was reduced tumor formation and lung metastasis. These data suggest that mitochondria are aberrant in LETM1-overexpressing osteosarcoma cells, and knockdown of LETM1 partially restores the mitochondrial structure and function, inhibits the pentose phosphate pathway, promotes oxidative phosphorylation, and increases osteogenic differentiation, thereby reducing malignant biological behavior of the cells.
Insights
Targeting Leucine-containing zipper and EF-hand transmembrane protein 1 (LETM1) in osteosarcoma cells can restore mitochondrial function and promote osteogenic differentiation. This approach inhibits tumor growth and metastasis, offering a potential new therapy for this bone cancer.
Area of Science:
- Oncology
- Cell Biology
- Mitochondrial Biology
Background:
- Osteosarcoma is a poorly differentiated bone cancer with limited therapeutic options.
- Differentiation therapy shows promise but lacks identified targets.
- Altered cellular metabolism, including impaired oxidative phosphorylation and increased pentose phosphate pathway activity, is common in cancer cells.
Purpose of the Study:
- To investigate the role of Leucine-containing zipper and EF-hand transmembrane protein 1 (LETM1) in osteosarcoma.
- To determine if targeting LETM1 can induce osteosarcoma cell differentiation and reduce malignancy.
Main Methods:
- Overexpression of LETM1 in MG63 and 143B osteosarcoma cell lines was analyzed.
- LETM1 was knocked down using experimental models.
- Mitochondrial structure and function, cellular metabolism (pentose phosphate pathway, oxidative phosphorylation), osteogenic differentiation, and cancer cell behavior (proliferation, migration, invasion, spheroid formation) were assessed.
- Tumor formation and lung metastasis were evaluated in vivo.
Main Results:
- Osteosarcoma cells (MG63, 143B) showed LETM1 overexpression and mitochondrial abnormalities.
- LETM1 knockdown partially restored mitochondrial structure and function.
- Knockdown inhibited the pentose phosphate pathway and promoted oxidative phosphorylation.
- LETM1 knockdown induced osteogenic differentiation and reduced proliferation, migration, invasion, and spheroid formation in vitro.
- In vivo, LETM1 knockdown reduced tumor formation and lung metastasis.
Conclusions:
- Aberrant mitochondria and LETM1 overexpression are characteristic of osteosarcoma.
- LETM1 knockdown partially normalizes mitochondrial function, shifts metabolism towards oxidative phosphorylation, and promotes osteogenic differentiation.
- Targeting LETM1 effectively reduces osteosarcoma cell malignancy and metastasis, suggesting its therapeutic potential.
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