Targeting the aryl hydrocarbon receptor/polyamine biosynthesis axis of evil for cancer therapy

Abstract

The polyamine metabolic pathway has been considered a rational target for antineoplastic therapy since it was discovered that polyamines are absolute requirements for tumor initiation, growth, and, in some instances, survival. Although several promising preclinical studies have demonstrated the critical nature of polyamines for tumor growth, the clinical success of agents targeting polyamine metabolism have been lacking. In the accompanying article, Bianchi-Smiraglia et al. identify both a new target and new drug that inhibits polyamine biosynthesis, reduces intracellular polyamines, and inhibits the growth of several models of human multiple myeloma. These results are both intriguing and provide promise for moving such a strategy to the clinic.

Polyamines and Kynurenines at the Intersection of Immune Modulation

“…Moreover, in human MM cells, AhR expression was reported to be inversely correlated with survival, suggesting that AhR inhibition is potentially beneficial for MM treatment, although this remains to be robustly tested [93]. Accordingly, in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts, clofazimine (an AhR antagonist) revealed high efficacy in reducing tumor growth relative to controls, which was comparable with that of bortezomib, a first-in-class proteasome inhibitor indication for MM therapy [93,94]. AhR activation can also upregulate the gene encoding SPDS in rat liver progenitor cells [95] and SMOX in human HepG2 cells [96], thus further favoring a positive spermidine/AhR feedback loop.…”

“…A new strategy to effectively block polyamine effects in tumors was recently described in multiple myeloma (MM) [93,94]. Specifically, in human MM cell cultures, AhR activation positively regulated intracellular polyamine production via direct transcriptional activation of ODC1 and AZIN1 [93].…”

“…Although addressed rarely together, kynurenines and polyamines (i.e., products derived from the degradation of -Try and -Orn, respectively) might be intimately linked to support tumor development and to suppress immune functions. In fact, these two pathways can potentiate each other via the transcription factor AhR in both human [94] and mouse cells [99].…”

Natural Product Quercetin-3-methyl ether Promotes Colorectal Cancer Cell Apoptosis by Downregulating Intracellular Polyamine Signaling

“…In the early stages of tumor transformation and progression, multiple carcinogenic pathways lead to polyamine demand and metabolic dysregulation 39 . At present, accumulating evidence suggests that polyamine metabolism is a target of anticancer therapy 55 , 56 . It is worth noting that SMOX ectopic expression in neuroblastoma cells increases oxidative DNA damage thus inducing apoptosis 57 .…”

Spermidine and spermine exert protective effects within the lung

“…In addition, spermidine via transformation into hypusine, promotes hypusination and, thus, activation of the critical cellular protein eukaryotic translation factor 5A (eIF5A) 25 . Spermidine can also promote dendritic cell immunoregulatory properties via the indoleamine 2,3‐dioxygenase 1 (IDO1) enzyme‐mediated conversion of tryptophan into kynurenines, suggesting an important immunoregulatory circuit involving the aryl hydrocarbon receptor (AhR) 19,26 . Thus, spermidine may exert immunomodulatory effects via both biochemical pathways and epigenetic modifications, which will need to be explored in future experiments focused on the inflamed lung and asthma.…”