TY - JOUR

T1 - Cell death induced by cationic amphiphilic drugs depends on lysosomal Ca2+ release and cyclic AMP

AU - Anand, Atul

AU - Liu, Bin

AU - Giacobini, Jano Dicroce

AU - Maeda, Kenji

AU - Rohde, Mikkel

AU - Jaattela, Marja

PY - 2019

Y1 - 2019

N2 - Repurposing cationic amphiphilic drugs (CAD) for cancer treatment is emerging as an attractive means to enhance the efficacy of chemotherapy. Many commonly used CADs, including several cation amphiphilic antihistamines and antidepressants, induce cancer-specific, lysosome-dependent cell death and sensitize cancer cells to chemotherapy. CAD-induced inhibition of lysosomal acid sphingomyelinase is necessary, but not sufficient, for the subsequent lysosomal membrane permeabilization and cell death, while other pathways regulating this cell death pathway are largely unknown. Prompted by significant changes in the expression of genes involved in Ca2+ and cyclic AMP (cAMP) signaling pathways in CAD-resistant MCF7 breast cancer cells, we identified here an early lysosomal Ca2+ release through P2X purinergic receptor 4 (P2RX4) and subsequent Ca2+- and adenylyl cyclase 1 (ADCY1)-dependent synthesis of cAMP as a signaling route mediating CAD-induced lysosomal membrane permeabilization and cell death. Importantly, pharmacologic and genetic means to increase cellular cAMP levels either by activating cAMP-inducing G-protein–coupled receptors (GPR3 or b2 adrenergic receptor) or ADCY1, or by inhibiting cAMP-reducing guanine nucleotide-binding protein G(i) subunit a2, C-X-C motif chemokine receptor type 4, or cAMP phosphodiesterases, sensitized cancer cells to CADs. These data reveal a previously unrecognized lysosomal P2RX4- and ADCY1-dependent signaling cascade as a pathway essential for CAD-induced lysosome-dependent cell death and encourage further investigations to find the most potent combinations of CADs and cAMP-inducing drugs for cancer therapy.

AB - Repurposing cationic amphiphilic drugs (CAD) for cancer treatment is emerging as an attractive means to enhance the efficacy of chemotherapy. Many commonly used CADs, including several cation amphiphilic antihistamines and antidepressants, induce cancer-specific, lysosome-dependent cell death and sensitize cancer cells to chemotherapy. CAD-induced inhibition of lysosomal acid sphingomyelinase is necessary, but not sufficient, for the subsequent lysosomal membrane permeabilization and cell death, while other pathways regulating this cell death pathway are largely unknown. Prompted by significant changes in the expression of genes involved in Ca2+ and cyclic AMP (cAMP) signaling pathways in CAD-resistant MCF7 breast cancer cells, we identified here an early lysosomal Ca2+ release through P2X purinergic receptor 4 (P2RX4) and subsequent Ca2+- and adenylyl cyclase 1 (ADCY1)-dependent synthesis of cAMP as a signaling route mediating CAD-induced lysosomal membrane permeabilization and cell death. Importantly, pharmacologic and genetic means to increase cellular cAMP levels either by activating cAMP-inducing G-protein–coupled receptors (GPR3 or b2 adrenergic receptor) or ADCY1, or by inhibiting cAMP-reducing guanine nucleotide-binding protein G(i) subunit a2, C-X-C motif chemokine receptor type 4, or cAMP phosphodiesterases, sensitized cancer cells to CADs. These data reveal a previously unrecognized lysosomal P2RX4- and ADCY1-dependent signaling cascade as a pathway essential for CAD-induced lysosome-dependent cell death and encourage further investigations to find the most potent combinations of CADs and cAMP-inducing drugs for cancer therapy.

U2 - 10.1158/1535-7163.MCT-18-1406

DO - 10.1158/1535-7163.MCT-18-1406

M3 - Journal article

C2 - 31285280

AN - SCOPUS:85071785143

VL - 18

SP - 1602

EP - 1614

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 9

ER -