BIX-01294-enhanced chemosensitivity in nasopharyngeal carcinoma depends on autophagy-induced pyroptosis

Abstract

Nasopharyngeal carcinoma (NPC) is a common cancer in southern China and Southeast Asia. Nowadays, radiotherapy is the therapy of choice for NPC patients, and chemotherapy has been found as an alternative treatment for advanced NPC patients. However, finding novel drugs and pharmacologically therapeutic targets for NPC patients is still urgent and beneficial. Our study showed that BIX-01294 (BIX) can induce autophagic vacuoles formation and conversion of LC3B-I to LC3B-II in NPC cells in both dose- and time-dependent manners. Notably, the combination of BIX and chemotherapeutic drugs significantly decreased the cell viability and increased the lactate dehydrogenase release. Meanwhile, BIX plus cis-platinum (Cis) treatment induced pyroptosis in NPC cells as featured by cell swelling and bubble blowing from the plasma membrane, the increased frequency of annexin V and propidium iodide (PI) double-positive cells, as well as the cleavage of gasdermin E (GSDME) and caspase-3. Moreover, the deficiency of GSDME completely shifted pyroptosis to apoptosis. Furthermore, the inhibition of autophagy by chloroquine and the knockout of ATG5 gene significantly blocked the BIX-induced autophagy as well as pyroptosis in both in vitro and in vivo studies. Our data demonstrated that BIX-combined chemotherapeutic drugs could induce the Bax/caspase-3/GSDME-mediated pyroptosis through the activation of autophagy to enhance the chemosensitivity in NPC.

Gasdermin E: A Prospective Target for Therapy of Diseases

“…By activating Bax/caspase-3/GSDME pathway-mediated pyroptosis, GW3064 enhances the chemosensitivity of oxaliplatin ( Guo et al, 2021 ). The enhancement of GSDME-dependent pyroptosis also corresponds to enhanced chemosensitivity in nasopharyngeal carcinoma and esophageal squamous cell carcinoma ( Li Q. et al, 2020 ; Zheng et al, 2021 ). Thus, the activation of pyroptosis driven by GSDME may be an important manner to eliminate tumor resistance.…”

Emerging mechanisms of pyroptosis and its therapeutic strategy in cancer

“…AA and ATO synergistically inhibit colorectal cancer cell growth by activating apoptosis and pyroptosis [ 129 ]. BIX-01294 combined with cisplatin treatment induces pyroptosis through a mechanism dependent on autophagy via the Bax/caspase-3/GSDME pathway and enhances the chemosensitivity of NPC [ 130 ]. The combination of oxaliplatin and GW4064 synergistically suppresses the growth and colony formation of colorectal cancer cells.…”

Pyroptosis patterns and immune infiltrates characterization in head and neck squamous cell carcinoma

“…Another is caspase‐4/5‐dependent nontypical inflammasome, in which pro‐caspase‐4/5 was activated by cytosolic bacterial lipopolysaccharide released by gram‐negative bacteria 7 . The pyroptosis pathway mediated by caspase‐3/GSDME is also associated with tumor chemotherapy 8,9 . In the pathway, caspase‐3 is spliced by Asp270, which converts cells that express GSDME noninflammatory apoptotic death into inflammatory pyroptotic death 10,11 .…”

“… 7 The pyroptosis pathway mediated by caspase‐3/GSDME is also associated with tumor chemotherapy. 8 , 9 In the pathway, caspase‐3 is spliced by Asp270, which converts cells that express GSDME noninflammatory apoptotic death into inflammatory pyroptotic death. 10 , 11 GSDMB or GSDMC might be spliced by caspase‐6 or caspase‐8 after tumor necrosis factor (TNF)‐mediated death receptor signaling to trigger pyroptosis, 12 while the process of activated GSDMA is currently unknown.…”