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PLOD3 suppression exerts an anti-tumor effect on human lung cancer cells by modulating the PKC-delta signaling

Jeong-Hwa Baek1,2, Hong Shik Yun1, Gyoo Taik Kwon1

  • 1Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, 01812, Korea.

Cell Death & Disease
|February 17, 2019
PubMed

Insights

Targeting procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) with siRNA inhibits lung cancer growth. PLOD3 knockdown overcomes chemoresistance and radioresistance by inducing apoptosis, suggesting PLOD3 as a therapeutic target and biomarker.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Lung cancer treatments require novel targets due to unsatisfactory outcomes.
  • Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) is implicated in fibrosis and tissue remodeling.
  • PLOD3 is identified as a radioresistance-related protein in lung cancer cells, but its mechanism remains unclear.

Purpose of the Study:

  • To investigate the role of PLOD3 in lung cancer radioresistance and chemoresistance.
  • To evaluate the therapeutic potential of targeting PLOD3 using short interfering (si)RNAs.
  • To elucidate the molecular mechanisms by which PLOD3 influences cancer cell apoptosis and treatment response.

Main Methods:

  • Design and application of human PLOD3-specific siRNAs.
  • In vitro and in vivo experiments to assess tumor growth inhibition.
  • Analysis of apoptosis pathways, including caspase activation and the unfolded-protein response (UPR).
  • Correlation analysis between PLOD3 expression and patient prognosis.

Main Results:

  • PLOD3 knockdown sensitized lung cancer cells to chemotherapy and radiotherapy by inducing caspase-3-dependent apoptosis.
  • PLOD3 interacts with PKCδ, activating caspase-2,4-dependent apoptosis via ER-stress-induced IRE1α activation and UPR.
  • PLOD3 siRNA significantly enhanced radiation-induced tumor growth inhibition in a mouse xenograft model without observable side effects.
  • High PLOD3 expression in lung cancer patients correlated with poorer prognosis following radiotherapy.

Conclusions:

  • PLOD3 plays a critical role in promoting lung cancer radioresistance and chemoresistance.
  • PLOD3 siRNA effectively suppresses tumor growth by inducing apoptosis, presenting a potential therapeutic strategy.
  • PLOD3 serves as a promising biomarker for predicting treatment response and patient prognosis in lung cancer.
  • Targeting PLOD3 offers a potential approach to enhance the efficacy of radiotherapy and chemotherapy in lung cancer patients.

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