Cycloheptylprodigiosin from marine bacterium Spartinivicinus ruber MCCC 1K03745T induces a novel form of cell death characterized by Golgi disruption and enhanced secretion of cathepsin D in non-small cell lung cancer cell lines

Prodiginines have been studied extensively for their Anticancer activity, however, the majority of the research has focused on prodigiosin. In this study, cycloheptylprodigiosin (S-1) is extracted from marine bacterium Spartinivicinus ruber MCCC 1K03745^T, and its Anticancer property was investigated. It exhibits remarkable cytotoxicity against a panel of human lung Cancer cell lines, with the IC₅₀ values ranging from 84.89 nM to 661.2 nM. After 6 h of treatment, S-1 gradually accumulates on mitochondria and lysosomes. While lower doses of S-1 induce cell cycle arrest, treatment with higher doses results in cell death in apoptotic independent manner in both NCI-H1299 and NCI-H460 cell lines. Interestingly, treatment with S-1 leads to the accumulation of LC3B-II via pathways that vary among different cell lines. In addition to its role as an Autophagy Inhibitor, S-1 also promotes Autophagy initiation as demonstrated by the increment of EGFP fragment in the EGFP-LC3 degradation assay, however, inhibition of Autophagy does not rescue cells from death induced by S-1. Mechanistically, S-1 impairs autophagic flux through disrupting acidic lysosomal pH and blocking the maturation of Cathepsin D. Moreover, treatment with S-1 enhanced secretion of both pro- and mature forms of Cathepsin D, coincident with disintegration of trans-Golgi network. Interestingly, S-1 does not induce Ferroptosis, Pyroptosis or Necroptosis in NCI-H1299 cells. However, treatment of NCI-H460 cells with S-1 induces methuosis, which can be suppressed by Rac1 inhibitor EHT 1864. Our data demonstrate that S-1 is an effective Anticancer agent with potential therapeutic application.

Anticancer; Apoptosis; Autophagy; Cathepsin D; Cycloheptylprodigiosin; Prodiginine.