HomeENGLISH MAGAZINEInterleukin-24: the forgotten anticancer weapon rolls the dice(R) to death

Interleukin-24: the forgotten anticancer weapon rolls the dice(R) to death

More than a decade of research on the IL-24 gene has shown that it helps to suppress a majority of cancer types, and now scientists are focusing on how the gene drives this process by influencing microRNAs. Published this week in the journal Proceedings of the National Academy of Sciences, the findings could potentially have implications beyond cancer for a variety of cardiovascular and neurodegenerative diseases caused by the same microRNA-driven processes. The study was led by Paul B. Fisher, MPh, PhD, chairman of the Department of Human and Molecular Genetics at VCU School of Medicine and director of the VCU Institute of Molecular Medicine (VIMM). The IL-24 gene was originally discovered by Fisher, and he and his colleagues have since published a number of studies detailing how the gene can suppress cancer by directly influencing two important mediators of cell death known as apoptosis and toxic autophagy. They have also been developing IL-24 viral gene therapies, purified protein treatments and T-cell-delivered therapies that take advantage of these processes to selectively kill cancer cells.

This study shows for the first time how IL-24 influences an enzyme critical to microRNA processing, and it provides exciting clues as to how this process could be targeted therapeutically. The researchers showed that IL-24 reduces the expression of an enzyme called DICER, and this effect occurs only in cancer cells. DICER works to process microRNAs for specific cellular functions. Dicer cleaves double-stranded RNA (dsRNA) and pre-microRNA (pre-miRNA) into short single-stranded RNA fragments called small interfering RNA and microRNA, respectively. In experiments involving prostate, breast and brain cancer cell lines and mouse models, overexpression of DICER by adenovirus was shown to rescue cancer cells from IL-24-mediated cell death. DICER is unchanged by Ad.mda-7/IL-24 in normal immortal prostate cells, whereas Ad.mda-7 down-regulates DICER in multiple cancer cells including glioblastoma, prostate, breast, lung and liver carcinoma cells. Previous experiments showed a potent bystander effect where IL-24 not only killed cancer cells at the primary tumor site but also in distant secondary tumors not directly targeted by the therapy.

The bystander effect is mediated, at least in part, by the potent immune activating and anti-growth properties of IL-24. These findings help explain why this bystander effect occurs. IL-24 down-regulates DICER expression through canonical IL-20/IL-22 receptors. Microphthalmia-associated transcription factor (MITF) was found to be a key mediator in this process. The scientists showed for the first time that IL-24 down-regulates MITF, which, in turn, down-regulates the target of MITF, that is DICER. MITF regulates cellular responses to reactive oxygen species (ROS), a natural byproduct of the normal oxidative metabolism and an important component in cell signaling. In times of cellular stress, ROS levels can increase dramatically and contribute to the development of diseases. It has already proven how MITF, that is responsible for retinal RPE cell development and function, regulates redox signaling by acting through PGC1α, a master regulator of mitochondrial biogenesis. Another protein possibly involved in MITF actions is Bcl-2, a known anti-death protein which has indirect antioxidant effects through localization in mitochondria.

Dr. Fisher concluded: “This is an exciting and previously unknown link between IL-24 and ROS/MITF/DICER that we plan to continue exploring. This research may open up new therapeutic targets, and monitoring the levels of these components could provide important biomarkers to help inform the effectiveness of IL-24-based therapies.”

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Pradhan AK et al. P.N.A.S. USA. 2019 Mar 19; 116(12):5687-5692. 

Goding CR. Pigment Cell Melanoma Res. 2010 Aug; 23(4):483-84. 

Levy C et al., Fisher DE. Cell 2010 Jun 11; 141(6):994-1005. 

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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