n-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide and Pancreatic-Neoplasms

Alkaliptosis, a type of regulated cell death driven by intracellular alkalization, was first described in pancreatic ductal adenocarcinoma (PDAC) cells after treatment with the opioid analgesic drug JTC801. Here, we used mass-spectrometry-based drug target identification, cellular thermal shift assay, and point mutation technologies to reveal ATP6V0D1 as a direct JTC801 target that drives alkaliptosis in human PDAC cells. Functionally, the protein stability of ATP6V0D1, when mediated by JTC801, increases the interaction between ATP6V0D1 and STAT3, resulting in increased expression and activity of STAT3 for sustaining lysosome homeostasis. Consequently, the pharmacological or genetic inhibition of STAT3 restores the sensitivity of ATP6V0D1-deficient cells to alkaliptosis in vitro or in suitable mouse models. Clinically, a high expression of ATP6V0D1 correlates with prolonged survival of patients with PDAC. Together, these results illustrate a link between ATP6V0D1 and PDAC and advance our understanding of alkaliptosis in targeted therapy.

Topics: Animals; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Homeostasis; Humans; Hydrogen-Ion Concentration; Lysosomes; Mice; Pancreatic Neoplasms; Signal Transduction; STAT3 Transcription Factor

Alkaliptosis is a recently discovered type of pH-dependent cell death used for tumor therapy. However, its underlying molecular mechanisms and regulatory networks are largely unknown. Here, we report that the acetate-activating enzyme acetyl-CoA short-chain synthase family member 2 (ACSS2) is a positive regulator of alkaliptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Using qPCR and western blot analysis, we found that the mRNA and protein expression of ACSS2 was upregulated in human PDAC cell lines (PANC1 and MiaPaCa2) in response to the classic alkaliptosis activator JTC801. Consequently, the knockdown of ACSS2 by shRNAs inhibited JTC801-induced cell death in PDAC cells, and was accompanied by an increase in cell clone formation and a decrease in intracellular pH. Mechanically, ACSS2-mediated acetyl-coenzyme A production and subsequent histone acetylation contributed to NF-κB-dependent CA9 downregulation, and this effect was enhanced by the histone deacetylase inhibitor trichostatin A. These findings may provide new insights for understanding the metabolic basis of alkaliptosis and establish a potential strategy for PDAC treatment.

Topics: Acetate-CoA Ligase; Aminoquinolines; Benzamides; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Humans; NF-kappa B; Pancreatic Neoplasms

Malignant tumors are one of the major causes of death worldwide, and the development of better treatments is urgently needed. There are many types of cancer treatment, such as surgery, chemotherapy, radiation therapy, immunotherapy, and targeted therapy, that might improve patient outcomes in a genotype- and stage-dependent manner. The main goal of cancer therapy is to inhibit biological capabilities of tumors and eventually eliminate the cancer cells. However, cancer cells are well known to escape apoptosis, a form of programmed cell death that was first described in studies of cell development and tissue remodelling. Increasing our understanding of cell death may result in new anticancer approaches that target types of nonapoptotic cell death, such as necroptosis, ferroptosis, autophagy-dependent cell death, and alkaliptosis. Notably, alkaliptosis, a pH-dependent form of regulated cell death, has been recently identified as a new strategy for cancer therapy across multiple tumor types, especially in pancreatic cancer.

Topics: Aminoquinolines; Antigens, Neoplasm; Antineoplastic Agents; Benzamides; Carbonic Anhydrase IX; Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Development; Humans; Hydrogen-Ion Concentration; NF-kappa B; Pancreatic Neoplasms; Regulated Cell Death; Signal Transduction