Hepatocellular carcinoma (HCC) is one of the most common and deadliest cancer in the world. Despite this, few effective drugs are available for its treatment, in part due to the development of resistance, and surgical resection remains the most valuable option, when applicable. Upregulation of anti-apoptotic proteins, downregulation of pro-apoptotic factors and the acquisition of mutations in signaling pathways leading to caspase activation are a few examples of mechanisms that allow cancer cells to evade caspase-dependent apoptosis and continue to grow. The identification of drugs triggering the activation of caspase-independent death may therefore be an effective strategy to circumvent resistance and kill cancer cells. Here, we show that the lysosome damaging compound glycyl-l-phenylalanine 2-naphthylamide (GPN) induces cell death by a caspase-independent mechanism in HCC cell lines. Additionally, we identify the MAPK p38 as a novel mediator of the lysosomal stress response. Indeed, a ROS-dependent activation of p38 occurs in response to lysosomal damage, promoting the recovery of lysosomal integrity. As a consequence, pharmacological or genetic inhibition of p38 increases cell death elicited by GPN. Our findings identify p38 as a potential target to potentiate the cytotoxic effects of lysosomal damage and induce caspase-independent cell death in HCC cells, laying the ground for future evaluation of the efficacy of combination therapy.

ROS-mediated activation of p38 protects hepatocellular carcinoma cells from caspase-independent death elicited by lysosomal damage

Desideri, Enrico
;
2022-01-01

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and deadliest cancer in the world. Despite this, few effective drugs are available for its treatment, in part due to the development of resistance, and surgical resection remains the most valuable option, when applicable. Upregulation of anti-apoptotic proteins, downregulation of pro-apoptotic factors and the acquisition of mutations in signaling pathways leading to caspase activation are a few examples of mechanisms that allow cancer cells to evade caspase-dependent apoptosis and continue to grow. The identification of drugs triggering the activation of caspase-independent death may therefore be an effective strategy to circumvent resistance and kill cancer cells. Here, we show that the lysosome damaging compound glycyl-l-phenylalanine 2-naphthylamide (GPN) induces cell death by a caspase-independent mechanism in HCC cell lines. Additionally, we identify the MAPK p38 as a novel mediator of the lysosomal stress response. Indeed, a ROS-dependent activation of p38 occurs in response to lysosomal damage, promoting the recovery of lysosomal integrity. As a consequence, pharmacological or genetic inhibition of p38 increases cell death elicited by GPN. Our findings identify p38 as a potential target to potentiate the cytotoxic effects of lysosomal damage and induce caspase-independent cell death in HCC cells, laying the ground for future evaluation of the efficacy of combination therapy.
2022
Caspase-independent death
Hepatocellular carcinoma
Lysosomal stress response
P38
Reactive oxygen species
Apoptosis
Caspases
Cell Line
Cell Line, Tumor
Humans
Lysosomes
Reactive Oxygen Species
p38 Mitogen-Activated Protein Kinases
Carcinoma, Hepatocellular
Liver Neoplasms
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12078/10807
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