Dataset Information

Mitochondrial division inhibitor (mdivi-1) decreases oxidative metabolism in cancer.

ABSTRACT:

Background

Previous studies suggested that mdivi-1 (mitochondrial division inhibitor), a putative inhibitor of dynamin-related protein (DRP1), decreased cancer cell proliferation through inducing mitochondrial fusion and altering oxygen consumption. However, the metabolic reprogramming underlying the DRP1 inhibition is still unclear in cancer cells.

Methods

To better understand the metabolic effect of DRP1 inhibition, [U-¹³C]glucose isotope tracing was employed to assess mdivi-1 effects in several cancer cell lines, DRP1-WT (wild-type) and DRP1-KO (knockout) H460 lung cancer cells and mouse embryonic fibroblasts (MEFs).

Results

Mitochondrial staining confirmed that mdivi-1 treatment and DRP1 deficiency induced mitochondrial fusion. Surprisingly, metabolic isotope tracing found that mdivi-1 decreased mitochondrial oxidative metabolism in the lung cancer cell lines H460, A549 and the colon cancer cell line HCT116. [U-¹³C]glucose tracing studies also showed that the TCA cycle intermediates had significantly lower enrichment in mdivi-1-treated cells. In comparison, DRP1-WT and DRP1-KO H460 cells had similar oxidative metabolism, which was decreased by mdivi-1 treatment. Furthermore, mdivi-1-mediated effects on oxidative metabolism were independent of mitochondrial fusion.

Conclusions

Our data suggest that, in cancer cells, mdivi-1, a putative inhibitor of DRP1, decreases oxidative metabolism to impair cell proliferation.

SUBMITTER: Dai W

PROVIDER: S-EPMC7188673 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Metabolic rewiring is a common feature of many cancer types, including prostate cancer (PCa). Alterations in master genes lead to mitochondrial metabolic rewiring and provide an appealing target to inhibit cancer progression and improve survival. Phospholipase C (PLC)? is a regulator of tumor generation and progression. However, its role in mitochondrial metabolism remains unclear. METHODS:The GEO, The Cancer Genome Atlas, and the GTEx databases were used to determine Twist1 mRNA levels in tumors and their non-tumor counterparts. Fifty-five PCa and 48 benign prostatic hypertrophy tissue samples were tested for the presence of PLC? and Twist1 immunohistochemically. An association between PLC? and Twist1 was determined by Pearson's correlation analysis. PLC? was knocked down with a lentiviral short hairpin RNA. Mitochondrial activity was assessed by measuring the oxygen consumption rate. Western blotting analyses were used to measure levels of PPAR?, Twist1, phosphorylated (p)-Twist1, p-MEK, p-ERK, p-P38, and p-c-Jun N-terminal kinase (JNK). Cells were treated with inhibitors of MEK, JNK, and P38 MAPK, and an agonist and inhibitor of peroxisome proliferator activated receptor (PPAR) ?, to evaluate which signaling pathways were involved in PLC?-mediated Twist1 expression. The stability of Twist1 was determined after blocking protein synthesis with cycloheximide. Reporter assays utilized E-cadherin or N-cadherin luciferase reporters under depletion of PLC? or Twist1. Transwell assays assessed cell migration. Finally, a nude mouse tumor xenograft assay was conducted to verify the role of PLC? in tumor formation. RESULTS:Our findings revealed that the expression of PLC? was positively associated with Twist1 in clinical PCa samples. PLC? knockdown promoted mitochondrial oxidative metabolism in PCa cells. Mechanistically, PLC? increased phosphorylation of Twist1 and stabilized the Twist1 protein through MAPK signaling. The transcriptional activity of Twist1, and the Twist1-mediated epithelial-to-mesenchymal transition, cell migration, and transcription regulation, were suppressed by PLC? knockdown and by blocking PPAR? nuclear translocation. The tumor xenograft assay demonstrated that PLC? depletion diminished PCa cell tumorigenesis. CONCLUSIONS:These findings reveal an undiscovered physiological role for PLC? in the suppression of mitochondrial oxidative metabolism that has significant implications for understanding PCa occurrence and migration.