Inhibition of LDHB triggers DNA damage and increases cisplatin sensitivity in pleural mesothelioma

Our plain-English summary of Inhibition of LDHB triggers DNA damage and increases cisplatin sensitivity in pleural mesothelioma, by Y. Lin, C. Dubey, T. Losmanova, et al (Oncogenesis, 2025).

The study

• Authors: Y. Lin, C. Dubey, T. Losmanova, S.O. Yasmin, J.L. Reymond, R.W. Peng, H. Deng, P. Dorn, T.M. Marti
• Journal: Oncogenesis
• Published: 2025;14(1):28
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pleural mesothelioma (PM) is an aggressive, asbestos-linked cancer with limited treatment options and a poor prognosis. Lactate dehydrogenase B (LDHB) converts lactate to pyruvate, and its silencing reduces mitochondrial metabolism, particularly nucleotide synthesis. However, whether and a role of LDHB in PM is unclear. This study aimed to investigate the effects of silencing LDHB in PM cells and their response to chemotherapy. LDHB was silenced using siRNA transfection and inducible shRNA constructs. Proliferation, colony formation, and cell viability were assessed, while DNA damage was analyzed through ɣH2AX levels. Compared to normal mesothelial cells, LDHB was highly expressed in PM cell lines. LDHB inhibition significantly reduced proliferation, cell viability, and colony formation, indicating its crucial role in PM cells. Additionally, LDHB silencing significantly increased nuclear DNA damage accumulation as indicated by elevated ɣH2AX levels, which was reversed by nucleotide supplementation. In vivo, LDHB inhibition reduced tumor growth and enhanced cisplatin's therapeutic efficacy. LDHB silencing increased ɣH2AX levels, which were further elevated with cisplatin treatment. Our results highlight LDHB as a novel therapeutic target in PM, where its inhibition induces DNA damage and improves the efficacy of cisplatin therapy.

© 2025. The Author(s).

In plain English

This was a laboratory study of pleural mesothelioma (PM) cells and mouse xenografts, not a study of people exposed to asbestos; asbestos is mentioned only as background. The authors silenced the gene for lactate dehydrogenase B (LDHB) with siRNA in MSTO-211H, MESO4 and H2052 cells, established doxycycline-inducible shRNA silencing in MSTO-211H and MESO4 cells, and implanted MSTO-211H cells into NSG mice. Compared with the immortalized mesothelial line MET-5A, all tested PM lines except MESO4 had significantly higher LDHB protein. In a TCGA PM patient dataset, high LDHB mRNA expression correlated with poorer overall survival (HR=1.9, p=0.000325). Silencing LDHB significantly reduced proliferation, cell viability and colony formation, and raised the DNA damage marker gamma-H2AX; nucleotide precursors partially mitigated the gamma-H2AX rise, partially rescued colony formation, and slightly increased viability in MSTO-211H cells and in MESO4 cells silenced with ishLDHB#1 but not with ishLDHB#2. At the time points tested, silencing did not significantly induce apoptosis or raise average ROS levels in the cell lines studied. Combining cisplatin with LDHB silencing further increased gamma-H2AX and further reduced tumour volume in mice compared with either treatment alone. The authors concluded that targeting LDHB could enhance chemotherapy-based combination therapies for PM.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory study in human mesothelioma cell lines plus a mouse xenograft experiment and analysis of public TCGA/GEO data
• Who was studied: Human pleural mesothelioma cell lines (MSTO-211H, MESO4, H2052, plus a panel including H28, JL-1, H2452, MESO-1) with the immortalized mesothelial line MET-5A as control; 8-week-old NSG mice bearing MSTO-211H xenografts (4-5 mice per group); TCGA PM patient cohort
• Exposure: Silencing of LDHB by siRNA and doxycycline-inducible shRNA, alone and combined with cisplatin (0.25-10 microM in vitro; 3 mg/kg i.p. in mice), pemetrexed (MTA), and supplementation with adenine, guanine, cytidine and uridine
• Main results:
  • siRNA silencing was tested in three PM cell lines (MSTO-211H, MESO4, H2052), reducing colony and sphere formation, proliferation and viability
  • Inducible shRNA silencing was established only in MSTO-211H and MESO4 cells
  • LDHB protein was significantly higher in all tested PM cell lines except MESO4 compared with the non-malignant mesothelial line MET-5A
  • In the TCGA PM patient cohort, high LDHB mRNA expression correlated with poor overall survival
  • Kaplan-Meier comparison of high versus low LDHB expression in the TCGA mesothelioma database
  • Doxycycline-induced LDHB silencing significantly decreased proliferation, viability and colony formation in MSTO-211H and MESO4 cells
  • LDHB silencing raised the DNA damage marker gamma-H2AX over time in both cell lines, with the highest levels in S-phase cells and increased nuclear foci
  • Nucleotide precursor supplementation slightly but significantly increased viability in MSTO-211H cells and in MESO4 cells silenced with ishLDHB#1, but not with ishLDHB#2 in MESO4
  • Nucleotide supplementation partially reduced the gamma-H2AX increase caused by LDHB silencing and partially rescued colony formation
  • LDHB inhibition did not significantly induce apoptosis at the time points tested
  • LDHB silencing lowered the oxygen consumption rate but did not significantly raise average ROS levels in the tested PM cell lines at the tested time points
  • Cisplatin combined with LDHB inhibition increased gamma-H2AX more than either treatment alone in MSTO-211H and MESO4 cells
  • Adding pemetrexed did not further reduce colony formation beyond LDHB inhibition alone or LDHB inhibition plus cisplatin
  • In the mouse xenografts, LDHB silencing reduced tumour growth without body weight loss, and the cisplatin combination further decreased tumour volume
  • In xenograft tissue, LDHB silencing reduced Ki-67-positive cells and, with cisplatin, further increased gamma-H2AX-positive cells
• The authors' conclusion: The authors concluded that LDHB is highly expressed in PM cell lines, that silencing it reduces proliferation, viability and colony formation and increases DNA damage, and that targeting LDHB could be a promising strategy to enhance chemotherapy-based combination therapies for PM
• Limitations the authors state:
  • The in vivo testing used only a subcutaneous tumour model in immunocompromised mice
  • The control mesothelial cell line MET-5A is immortalized; primary non-immortalized mesothelial cells would be a more physiologically relevant control
  • The proposed link between LDHB inhibition and DHODH-mediated thymidine synthesis remains speculative and unconfirmed
  • Whether apoptosis-independent cell death pathways such as senescence or ferroptosis contribute was not determined

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Pleural Mesothelioma, Prognosis, Lactate Dehydrogenase (LDH), Chemotherapy, Mesothelial Cells.

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