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SPINK13 acts as a tumor suppressor in hepatocellular carcinoma by inhibiting Akt phosphorylation

Yongzhi Lun1,2, Jie Sun3,4, Ling Wei5

  • 1Key Laboratory of Screening and Control of Infectious Diseases, Fujian Provincial University, Quanzhou Medical College, Quanzhou, 362011, Fujian, China. lunyz@163.com.

Cell Death & Disease
|November 13, 2024
PubMed

Insights

SPINK13 induces apoptosis in hepatocellular carcinoma by inhibiting the PI3K/Akt pathway. This novel mechanism involves the Notch1/Hes1/PTEN pathway, offering a new target for cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The PI3K/Akt pathway is frequently overexpressed in hepatocellular carcinoma (HCC), promoting tumor growth and inhibiting apoptosis.
  • Serine protease inhibitors show potential in inducing apoptosis in hepatoma cells, partly by downregulating SPINK13 within the PI3K/Akt pathway.

Purpose of the Study:

  • To elucidate the mechanism by which endogenous SPINK13 induces apoptosis in HCC cells.
  • To investigate the role of SPINK13 in regulating signaling pathways and cellular behavior in HCC models.

Main Methods:

  • SPINK13 was expressed using lentiviral vectors in HCC cell lines and nude mouse xenograft models.
  • Changes in signaling proteins, apoptosis regulators, cell cycle proteins, and tumor behavior were analyzed.
  • Transcriptomics was employed to explore the molecular mechanisms of SPINK13-induced apoptosis.

Main Results:

  • Endogenous SPINK13 was found to inhibit Furin protease activity and downregulate the Notch1/Hes1 pathway.
  • SPINK13 activates PTEN, leading to inhibition of Akt phosphorylation and inactivation of the PI3K/Akt pathway.
  • These events ultimately result in mitochondrial apoptosis and cell cycle arrest in hepatoma cells.

Conclusions:

  • The Notch1/Hes1/PTEN pathway acts upstream of SPINK13 to modulate the PI3K/Akt signaling pathway in HCC.
  • SPINK13 plays a crucial role in anti-HCC activity by targeting the PI3K/Akt pathway.
  • This study provides a theoretical basis for developing new serine protease inhibitors for HCC treatment.

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