Targeting Src reactivates pyroptosis to reverse chemoresistance in lung and pancreatic cancer models

Abstract

Pancreatic and lung cancers frequently develop resistance to chemotherapy-induced cell apoptosis during the treatment, indicating that targeting nonapoptotic-related pathways, such as pyroptosis, can be an alternative cancer treatment strategy. Pyroptosis is a gasdermin-driven lytic programmed cell death triggered by inflammatory caspases when initiated by canonical or noncanonical pathways that has been recently seen as a potential therapeutic target in cancer treatment. However, overcoming chemoresistance in cancers by modulating pyroptosis has not been explored. Here, we demonstrate that β5-integrin represses chemotherapy-induced canonical pyroptosis to confer cancer chemoresistance through ASAH2-driven sphingolipid metabolic reprogramming. Clinically, high β5-integrin expression associates with poor patient prognosis and chemotherapeutic responses in cancers. In addition, chemoresistant cells in vitro fail to undergo chemotherapy-induced pyroptosis, which is controlled by β5-integrin. Mechanistically, proteomic and lipidomic analyses indicate that β5-integrin up-regulates sphingolipid metabolic enzyme ceramidase (ASAH2) expression through Src–signal transducer and activator of transcription 3 (STAT3) signaling, which then reduces the metabolite ceramide concentration and subsequent ROS production to prohibit chemotherapy-induced canonical pyroptosis. Using cancer cell lines, patient-derived tumor organoids, and orthotopic lung and pancreatic animal models, we show that administration of a Src or ceramidase inhibitor rescues the response of chemoresistant pancreatic and lung cancer cells to chemotherapy by reactivating pyroptosis in vitro and in vivo. Overall, our results suggest that pyroptosis-based therapy is a means to improve cancer treatment and warrants further investigation.

Knocking down GALNT6 promotes pyroptosis of pancreatic ductal adenocarcinoma cells through NF-κB/NLRP3/GSDMD and GSDME signaling pathway

“…Pyroptosis-aroused immunological responses could convert immunosuppressive "cold" tumor microenvironment (TME) to immunogenic "hot" TME, which not only inhibits primary pancreatic cancer growth but also attacks the distant tumor (39). Pancreatic cancers frequently develop resistance to chemotherapy-induced cell apoptosis during the treatment, that targeting pyroptosis can be an alternative cancer treatment strategy (40). SEM results showed that knockdown of GALNT6 promoted the pyroptosis of PDAC cells.…”

Bone marrow adipocytes and lung cancer bone metastasis: unraveling the role of adipokines in the tumor microenvironment

“…For instance, proteins of the Bcl-2 family can inhibit the apoptosis of lung cancer cells and promote the differentiation and function of OCs. Cytokines released during the apoptosis of lung cancer cells, such as TNF-α, TGF-β, and VEGF, can indirectly promote bone metastasis by fostering inflammation and angiogenesis within the tumor microenvironment ( 75 ). Additionally, the release of lactate and ATP post-apoptosis can upregulate the metabolic state of bone cells and increase acidification of the tumor microenvironment, indirectly facilitating bone resorption in the context of lung cancer bone metastasis ( 76 ).…”

Emerging roles of 3D-culture systems in tackling tumor drug resistance

“…This effect is mediated through the upregulation of the sphingolipid metabolic enzyme ceramidase (ASAH2) expression, which is regulated by the STAT3 signaling pathway. The increased ceramidase expression results in a reduction of the metabolite ceramide concentration and subsequent suppression of reactive oxygen species (ROS) production, effectively blocking chemotherapy-induced canonical pyroptosis [ 70 ] .…”