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Abrogating PDK4 activates autophagy-dependent ferroptosis in breast cancer via ASK1/JNK pathway

Wenbiao Shi1, Jian Wang1, Jianbin Chen1

  • 1Department of Surgical Oncology, Taizhou Municipal Hospital, No.381 Zhongshan East Road, Jiaojiang District, Taizhou City, 318000, Zhejiang Province, China.

Journal of Cancer Research and Clinical Oncology
|April 27, 2024
PubMed
Abstract

Insights

Pyruvate dehydrogenase kinase isozyme 4 (PDK4) deficiency promotes autophagy-dependent ferroptosis in breast cancer by activating the ASK1/JNK pathway. This finding offers a new therapeutic strategy for breast cancer treatment.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Breast cancer is a global health concern.
  • Targeting ferroptosis, a cell death pathway regulated by autophagy, is a promising therapeutic strategy.
  • Pyruvate dehydrogenase kinase isozyme 4 (PDK4) plays a role in breast cancer metabolism.

Purpose of the Study:

  • To investigate the role of PDK4 in autophagy-dependent ferroptosis in breast cancer.
  • To elucidate the underlying molecular mechanisms of PDK4's function.

Main Methods:

  • Quantitative real-time PCR (RT-qPCR) and Western blotting to assess PDK4 expression.
  • Immunofluorescence staining for light chain 3 (LC3) to evaluate autophagy.
  • Iron assays and lipid peroxidation staining to measure ferroptosis.
  • Assays for reactive oxygen species (ROS) and Western blotting for pathway analysis (ASK1/JNK).

Main Results:

  • PDK4 was found to be highly expressed in breast cancer cells.
  • PDK4 knockdown induced autophagy and ferroptosis, which was partially reversed by an autophagy inhibitor (3-MA).
  • PDK4 knockdown activated the ASK1/JNK pathway, and inhibition of ASK1 partially blocked these effects.

Conclusions:

  • PDK4 deficiency stimulates autophagy-dependent ferroptosis in breast cancer.
  • The ASK1/JNK pathway is involved in mediating the effects of PDK4 on autophagy and ferroptosis.
  • These findings highlight PDK4 as a potential therapeutic target for breast cancer.
Keywords:
ASK1/JNK pathwayAutophagyBreast cancerFerroptosisPDK4

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