Exploiting Organelle Ion Dysregulation by Bacterial Natural Products to Target Cancer-Specific Vulnerabilities

Abstract

While the maintenance of ionic homeostasis is essential for all living cells, cancer cells strategically reprogram ionic signaling to sustain uncontrolled proliferation, metabolic flexibility, and resistance to cell death. Gradients and fluxes of key physiological ions, including Ca²⁺, Mg²⁺, Cl⁻, K⁺, and H+, regulate intracellular signaling pathways, gene expression networks, and inter-organelle communication. Disruption of these gradients can therefore compromise cancer cell viability, positioning ion regulation as an emerging and mechanistically tractable therapeutic vulnerability.

Bacterial natural products constitute a structurally diverse reservoir of natural compounds with potent anticancer properties. Although their cytotoxic effects are well documented, the molecular pathways through which they induce cancer cell death remain insufficiently understood. Notably, a subset of bacterial metabolites exhibits ionophoric behavior, directly transporting ions across biological membranes. Moreover, many metabolites bear aromatic or heteroaromatic cores with the potential to alter ion channel function or provoke localized ionic disturbances. Despite these mechanistic implications, direct evidence linking bacterial secondary metabolites to ion dysregulation–driven cancer cell death is limited, highlighting a critical gap in current knowledge.

In this dissertation, I characterize two representative bacterial metabolites—violacein and prodigiosin—as model compounds to elucidate how natural compounds exploit ionic vulnerabilities in cancer cells. I demonstrate that violacein induces pronounced cytoplasmic vacuolization and non- apoptotic cell death by interfering with lysosomal Ca²⁺ signaling. In contrast, prodigiosin operates as a chloride ionophore that elevates intracellular Cl⁻, resulting in excessive ER and mitochondrial Ca²⁺ accumulation and sequential activation of ER stress responses and intrinsic apoptotic cascades.

In conclusion, this work reveals that specific bacterial secondary metabolites can disrupt intracellular ion equilibrium to elicit organelle stress and promote cancer cell death. These findings provide a mechanistic basis for the development of ion-targeting anticancer therapeutics derived from microbial natural products, forging conceptual links between microbial chemistry, ion signaling, and tumor biology.