Activation of Lysosomal Retrograde Transport Triggers TPC1‐IP3R1 Ca 2+ Crosstalk at Lysosome‐ER MCSs Leading to Lethal Depleting of ER Calcium

Inter-organellar signaling linkages in oncology are increasingly elucidated. However, the impact of lysosome-endoplasmic reticulum (ER) interaction on tumor cell fate remains relatively unexplored. A novel interaction between lysosomes and the ER, mediated by the flavonoid LW-213 through targeting LIMP2 (lysosomal integral membrane protein type 2)to activate a lysosomal repair pathway, is identified in acute myeloid leukemia (AML). This leads to activated RAB7A activity, enhancing lysosomal retrograde transport to the perinuclear region and increasing contact at lysosome-ER membrane contact sites (MCSs). Close proximity of TPC1 to IP3R1 at these sites generates a concentrated calcium microdomain, triggering Ca²⁺-induced Ca²⁺ release, which causes cytoplasmic calcium turbulence and two distinct calcium tides. This excessive calcium efflux depletes ER calcium stores, triggering lethal ER stress-induced apoptosis. Interestingly, altering TPC1 expression levels in HeLa cells affected these calcium dynamics, replicating AML-specific mechanisms when overexpressed. Subsequent studies using BALB/c xenograft models with wild-type and LIMP2-knockout THP1 cells, along with ICR mice toxicity models, confirmed LW-213's significant tumor growth inhibition with minimal toxicity. These findings underscore the potential of targeting lysosomal-ER calcium crosstalk as an innovative approach to cancer treatment, highlighting the therapeutic promise of LW-213 in managing tumor cell fate through modulating organellar interactions.