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Plasminogen Activator Inhibitor-1 Secretion by Autophagy Contributes to Melanoma Resistance to Chemotherapy through

Hong-Tai Tzeng1, Jenq-Lin Yang1, Yu-Ju Tseng2

  • 1Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.

Cancers
|April 3, 2021
PubMed

Insights

Chemotherapy resistance in melanoma can be overcome by inhibiting autophagy-dependent plasminogen activator inhibitor-1 (PAI-1) secretion. Targeting tumor autophagy or PAI-1 enhances antitumor immunity and repurposes mitoxantrone for melanoma treatment.

Area of Science:

  • Cellular Biology
  • Cancer Research
  • Immunology

Background:

  • Autophagy is vital for cellular homeostasis but its role in chemotherapy resistance is unclear.
  • Dysregulated autophagy contributes to cancer development and treatment failure.
  • Mechanisms of autophagy-dependent secretion in chemotherapy response require further investigation.

Purpose of the Study:

  • To investigate the role of autophagy-dependent secretion in melanoma's response to mitoxantrone (MitoX).
  • To explore PAI-1 secretion as a mediator of the tumor microenvironment in response to chemotherapy.
  • To evaluate strategies for overcoming MitoX resistance in melanoma.

Main Methods:

  • Induction of autophagy in melanoma cells using mitoxantrone (MitoX) in vitro and in vivo.
  • Assessment of plasminogen activator inhibitor-1 (PAI-1) secretion and its impact on the tumor microenvironment.
  • Inhibition of PAI-1 activity with tiplaxtinin (TPX) or by targeting the autophagy gene Becn1.

Main Results:

  • MitoX induced autophagy and PAI-1 secretion in melanoma cells, promoting a pro-tumoral microenvironment.
  • Inhibiting PAI-1 or Becn1 restored antitumor immunity and overcame MitoX resistance.
  • TPX efficacy was dependent on Becn1 in MitoX-treated tumors.

Conclusions:

  • Tumor autophagy-driven PAI-1 secretion hinders mitoxantrone efficacy in melanoma.
  • Targeting tumor autophagy or PAI-1 presents a novel strategy to enhance mitoxantrone chemotherapy for melanoma.
  • This approach could repurpose existing chemotherapy agents for improved melanoma treatment outcomes.
Keywords:
autophagychemotherapymelanomaplasminogen activator inhibitor-1tumor microenvironment

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