Plasminogen Activator Inhibitor-1 Secretion by Autophagy Contributes to Melanoma Resistance to Chemotherapy through Tumor Microenvironment Modulation.

Abstract

Simple SummaryDysregulation of tumor autophagy is implicated in cancer progression and chemotherapeutic response. It is unclear how tumor autophagy modulates tumor microenvironment and thereby contributes to chemoresistance. In this study, we found that autophagy-dependent plasminogen activator inhibitor (PAI)-1 secretion contributed to melanoma resistance to mitoxantrone (MitoX), a chemotherapeutic agent clinically used for treating various types of cancers (but not melanoma), by shaping a pro-tumoral microenvironment. Disruption of autophagy activity or targeting PAI-1 pharmacologically reshaped a tumor-suppressive immune microenvironment and enhanced the susceptibility of melanoma to MitoX in vivo. Overall, the results show that targeting autophagy/PAI-1 axis can serve as a novel strategy to repurpose MitoX-based chemotherapy.Autophagy plays a crucial role in maintenance of cellular homeostasis via intracellular signaling pathways, lysosomal degradation of selective cargo and mediating protein secretion. Dysregulation of autophagy has been implicated in tumorigenesis, tumor progression, and resistance to therapy. However, the mechanism of autophagy-dependent secretion involved in the responsiveness to chemotherapy is poorly understood. In this study, we showed that mitoxantrone (MitoX), a chemotherapeutic agent used for treating various cancers but not melanoma, induced autophagy in melanoma cells in vitro and in vivo. We also found that plasminogen activator inhibitor (PAI)-1 secretion by MitoX-induced autophagy modulated the pro-tumoral microenvironment. Attenuation of PAI-1 activity using a specific inhibitor, tiplaxtinin (TPX), or by targeting the autophagy gene, Becn1, induced efficient antitumor immunity, thereby overcoming the resistance to MitoX in vivo. Of note, the therapeutic efficacy of TPX was abolished in MitoX-treated Becn1-defective tumors. Collectively, our results demonstrate that tumor autophagy-dependent PAI-1 secretion impairs the therapeutic efficacy of MitoX and highlight targeting of tumor autophagy or its secretory cargo, PAI-1, as a novel strategy to repurpose MitoX-based chemotherapy for melanoma treatment.