Mechanisms of alkaliptosis

Abstract

Malignant tumors represent a major threat to global health and the search for effective treatments is imperative. While various treatments exist, including surgery, radiotherapy, chemotherapy, immunotherapy and combination therapies, there remains a need to develop therapies that target regulated cell death pathways to eliminate cancer cells while preserving normal cells. Alkaliptosis, a pH-dependent cell death process triggered by the small molecular compound JTC801, has been identified as a novel approach for malignant tumor treatment, particularly in pancreatic cancer. Two major signaling pathways, the NF-κB-CA9 pathway and the ATP6V0D1-STAT3 pathway, contribute to the induction of alkaliptosis. This review summarizes recent developments in our understanding of alkaliptosis signals, mechanisms, and modulation, and explores its context-dependent effects on drug resistance, inflammation, and immunity. By providing a deeper understanding of the heterogeneity and plasticity of cell death mechanisms, this information holds promise for informing the design of more effective anti-tumor therapies.

Keywords: alkaliptosis; cancer; cell death; immunity; pH.

FIGURE 1

The core molecular mechanisms of alkaliptosis. The molecular mechanisms underlying alkaliptosis involve pH-induced alkalization, mainly through the activation of JTC801, which promotes the transcriptional repression of CA9 by NF-κB. JTC801 also induces acetylation of NF-κB by ACSS2, leading to alkaliptosis. The action of JTC801 results in the acidification of lysosomes or the extracellular environment, resulting in cytosolic alkalinization. Conversely, TMEM175 mediates lysosomal proton transport to the cytosol. The suppression of pH regulators, such as SLC9A7 or SLC9A1, also results in alkalization-related cell death. Targeting SLC4A4 or SLC7A5 can also induce pH-dependent cell death. Abbreviation. IKBKB, inhibitor of nuclear factor-κB kinase subunit-β; ATP6V0D1, ATPase H⁺ transporting V0 subunit D1; SLC9A1, solute carrier family 9 member A1; SLC9A7, solute carrier family 9 member A7; TMEM175, transmembrane protein 175; RELA, RELA proto-oncogene, NF-KB subunit; IKBKG, inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; CHUK, component of inhibitor of nuclear factor kappa B kinase complex; NFKBIA, NFKB inhibitor alpha; NFKB1, nuclear factor kappa B subunit 1; CA9, carbonic anhydrase 9; ACSS2, acyl-CoA synthetase short chain family member 2; SLC7A5, solute carrier family 7 member 5; SLC4A4, solute carrier family 4 member 4.

FIGURE 2

Mechanisms of alkaliptosis in drug resistance and immune response. (A) JTC801-induced alkaliptosis in venetoclax-resistant acute myeloid leukemia cells is mediated by the NF-κB-CA9 pathway. (B) Alkaliptotic cells secrete HMGB1, which binds to the receptor AGER of macrophages and triggers the STING1 pathway to initiate inflammation and an immune response. In contrast, FANCD2 suppresses HMGB1 release. Abbreviation. AML, acute myeloid leukemia; HMGB1, high mobility group box protein B1; AGER, advanced glycation end-product-specific receptor; STING1, stimulator of interferon response cGAMP interactor 1, FANCD2, FA complementation group D2.