Pharmacological inhibition of heme synthesis counteracts tumor growth

Heme can regulate its own synthesis modulating the expression of aminolevulinic acid synthase (ALAS1), the rate-limiting enzyme in its biosynthetic pathway. It is known that Feline leukemia virus subgroup C cellular receptor 1a (FLVCR1a) silencing increases the cytosolic free heme pool causing ALAS1 inhibition. This inhibition impairs tumor growth in colon rectal cancer and synovial sarcoma and impairs survival in SHSY5Y human neuroblastoma cells. Despite these promising results, no inhibitors of FLVCR1a are currently available. In this work, we aimed at identifying a valid pharmacological alternative, able to mimic FLVCR1a depletion phenotype. We showed how ALA, the product of ALAS1 was able to induce de novo synthetized heme accumulation within SHSY5Y cells. This led to heme synthesis inhibition, phenocopying FLVCR1a silencing. Interestingly, FLVCR1a resulted downmodulated upon the treatment. Consistently, ALA-induced heme synthesis inhibition caused a significant impairment of cancer cells proliferation and survival. Moreover, the Endoplasmic Reticulum (ER) stress marker GRP78/BIP and the pro-apoptotic transcription factor CHOP resulted upregulated in ALA-treated neuroblastoma cells, suggesting the involvement of ER stress in reduced proliferation/survival of treated cells. These data indicate that the pharmacological inhibition of heme synthesis might represent a valid approach to counteract tumor growth. Additional studies are required to test this treatment efficacy in vivo on neuroblastoma models.