Dataset Information

Functional heterogeneity of MCT1 and MCT4 in metabolic reprogramming affects osteosarcoma growth and metastasis.

ABSTRACT:

Background

Osteosarcoma is the most common primary malignant bone tumor in adolescents and children and prone to develop lung metastasis. Its prognosis has been virtually unimproved over the last few decades, especially in patients with metastases, who suffer from a dismal survival. Recently, increasing attention has been devoted to monocarboxylate transporters-related (MCTs) metabolic reprogramming. However, the role of MCT1 and MCT4 in osteosarcoma progression and the underlying mechanisms remain to be further elucidated.

Methods

In this study, we established MCT1 and/or MCT4 knockout cell lines by CRISPR/Cas9 genome editing technology. Then, we assessed glycolysis and oxidative phosphorylation capacities by measuring lactate flux and oxygen consumption. We also performed flowcytometry to test circulating tumor cells and PET/CT to evaluate glucose uptake.

Results

MCT1 was found to be involved in both glycolysis and oxidative respiration due to its ability to transport lactate in both directions. MCT1 inhibition significantly reduced circulating tumor cells and distant metastases partially by increasing oxidative stress. MCT4 was primarily related to glycolysis and responsible for lactate export when the concentration of extracellular lactate was high. MCT4 inhibition dramatically suppressed cell proliferation in vitro and impaired tumor growth with reduction of glucose uptake in vivo.

Conclusions

Our results demonstrate the functional heterogeneity and redundancy of MCT1 and MCT4 in glucose metabolism and tumor progression in osteosarcoma. Thus, combined inhibition of MCT1 and MCT4 may be a promising therapeutic strategy for treating tumors expressing both transporters.

SUBMITTER: Sheng G

PROVIDER: S-EPMC9948327 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Functional heterogeneity of MCT1 and MCT4 in metabolic reprogramming affects osteosarcoma growth and metastasis.

Sheng Gaohong G Gao Yuan Y Wu Hua H Liu Yang Y Yang Yong Y

Journal of orthopaedic surgery and research 20230222 1

<h4>Background</h4>Osteosarcoma is the most common primary malignant bone tumor in adolescents and children and prone to develop lung metastasis. Its prognosis has been virtually unimproved over the last few decades, especially in patients with metastases, who suffer from a dismal survival. Recently, increasing attention has been devoted to monocarboxylate transporters-related (MCTs) metabolic reprogramming. However, the role of MCT1 and MCT4 in osteosarcoma progression and the underlying mechan ...[more]

PMID: 36814318

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Project description:Many cancers rely on glycolytic metabolism to fuel rapid proliferation. This has spurred interest in designing drugs that target tumor glycolysis such as AZD3965, a small molecule inhibitor of Monocarboxylate Transporter 1 (MCT1) currently undergoing Phase I evaluation for cancer treatment. Since MCT1 mediates proton-linked transport of monocarboxylates such as lactate and pyruvate across the plasma membrane (Halestrap and Meredith, 2004), AZD3965 is thought to block tumor growth through disruption of lactate transport and glycolysis. Here we show that MCT1 inhibition impairs proliferation of glycolytic breast cancer cells that express MCT4 via disruption of pyruvate rather than lactate export. We found that MCT1 expression is elevated in glycolytic breast tumors and cell lines as well as in malignant breast and lung tissues. High MCT1 expression predicts poor prognosis in breast and lung cancer patients. Stable knockdown and AZD3965-mediated inhibition of MCT1 promote oxidative metabolism. Acute inhibition of MCT1 reduces pyruvate export rate but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that also express MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest that MCT1 expression is elevated in glycolytic cancers to promote pyruvate export, which when inhibited enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors that further supports their use as anti-cancer therapeutics. Since MCT1 levels are elevated in glycolytic and malignant breast tumors, we hypothesized that MCT1 may contribute to the Warburg effect metabolic phenotype. To test this hypothesis, we generated whole genome microarray data from breast cancer cell lines either a) expressing a short hairpin (sh)RNA-mediated stable knockdown of MCT1; or b) treated for 24 hours with an MCT1 inhibitor (AZD3965). Scramble shRNA or DMSO were used as controls, and all conditions were analzed in triplicate. The cell lines used â HS578T, SUM149PT, and SUM159PT â are among the most glycolytic in a panel of 31 breast cancer cell lines.

Dataset Information

Functional heterogeneity of MCT1 and MCT4 in metabolic reprogramming affects osteosarcoma growth and metastasis.

Background

Methods

Results

Conclusions

Publications

Functional heterogeneity of MCT1 and MCT4 in metabolic reprogramming affects osteosarcoma growth and metastasis.

Similar Datasets

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