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Dutomycin Induces Autophagy and Apoptosis by Targeting the Serine Protease Inhibitor SERPINB6

Mina Jang1,2, Shuta Hara3, Gun-Hee Kim1

  • 1Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116, Korea.

ACS Chemical Biology
|February 1, 2021
PubMed

Insights

Dutomycin (DTM) enhances autophagy, leading to cancer cell apoptosis. This novel drug targets human serine protease inhibitor B6 (SERPINB6), reducing tumor size in zebrafish models and offering new anticancer therapy strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Autophagy is crucial for tumor cell survival under metabolic stress.
  • Regulating autophagy presents a potential anticancer therapy strategy.
  • The role of human serine protease inhibitor B6 (SERPINB6) in autophagy and cancer is unexplored.

Purpose of the Study:

  • To identify novel autophagy enhancers for cancer therapy.
  • To investigate dutomycin (DTM) as an autophagy enhancer.
  • To elucidate the role of SERPINB6 in autophagy and its interaction with DTM.

Main Methods:

  • Enzyme- and cell-based assays to confirm DTM's inhibitory effects on SERPINB6.
  • siRNA-mediated knockdown and overexpression tests to validate SERPINB6 as a DTM target.
  • Zebrafish xenograft model to assess DTM's in vivo anticancer efficacy.

Main Results:

  • Dutomycin (DTM) was identified as a novel autophagy enhancer.
  • DTM directly binds and activates intracellular serine proteases via SERPINB6, inducing autophagy.
  • DTM demonstrated significant tumor area reduction in a zebrafish xenograft model.
  • SERPINB6 was validated as a direct target protein of DTM involved in autophagy.

Conclusions:

  • DTM induces cancer cell apoptosis through excessive autophagy by targeting SERPINB6.
  • This study reveals a novel function of SERPINB6 in autophagy.
  • The findings expand knowledge on cancer-autophagy correlation and suggest SERPINB6 as a potential therapeutic target.

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