Deficiency of δ‐Aminolevulinate Dehydratase Confers a Survival Advantage and Drives Malignancy in Cancer

Heme synthesis has been considered essential, yet cancer cells paradoxically maintain high proliferation despite suppressing the pathway, with low expression of δ-aminolevulinate dehydratase (ALAD), the second enzyme of the pathway, which correlates with a poor prognosis. We propose that this suppression is a novel survival strategy to avoid toxic intermediates. Supporting this, we observed that cancer cells vigorously grow after the complete knockout of the essential ALAD gene, demonstrating the pathway's non-essentiality in malignancy. This ALAD suppression offers a dual advantage: evading growth suppression and promoting malignant phenotypes (epithelial-mesenchymal transition). Crucially, the toxicity induced by reactivating the pathway is not dependent on conventional porphyrin (PpIX) or reactive oxygen species, but rather on an unknown intermediate metabolite upstream of PpIX. Activating the heme pathway, for example, by administration of its starting substrate 5-aminolevulinic acid, provides the impetus for a new therapeutic approach to break this defense.