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Curr Med Chem. 2019;26(33):6020-6032. doi: 10.2174/0929867326666181203133332.

Targeting the Ribosome Biogenesis Key Molecule Fibrillarin to Avoid Chemoresistance.

Author information

1
Department of Medical Oncology, VU University Medical Center- Cancer Center Amsterdam, De Boelelaan 1118, 1081 HV Amsterdam, Netherlands.
2
AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University Amsterdam, O|2 building, De Boelelaan 1108, 1081 HZ Amsterdam, Netherlands.
3
Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa, Italy.

Abstract

BACKGROUND:

Inherent or acquired chemo resistance in cancer patients has been a perpetual limitation in cancer treatment. Expanding knowledge on essential cellular processes opens a new window for therapeutic targeting. Ribosome biogenesis is a process that shows potential due to its fundamental role in cell development and contribution to tumorigenesis as a result of its upregulation. Inhibiting components of ribosome biogenesis has been explored and has shown interesting results. Yet, an important key component, methyltransferase Fibrillarin (FBL), which influences both the abundance and composition of ribosomes, has not been exploited thus far.

METHODS:

In this literature review, we describe relevant aspects of ribosome biogenesis in cancer to emphasize the potential of FBL as a therapeutic target, in order to lower the genotoxic effects of anti-cancer treatment.

RESULTS:

Remarkably, the amplification of the 19q13 cytogenetic band, including the gene coding for FBL, correlated to cell viability and resistance in pancreatic cells as well as to a trend toward a shorter survival in pancreatic cancer patients. Targeting ribosome biogenesis, more specifically compared to the secondary effects of chemotherapeutics such as 5-fluorouracil or oxaliplatin, has been achieved by compound CX-5461. The cell dependent activity of this Pol I inhibitor has been reported in ovarian cancer, melanoma and leukemia models with active or mutated p53 status, presenting a promising mechanism to evade p53 resistance.

CONCLUSION:

Targeting critical ribosome biogenesis components in order to decrease the genotoxic activity in cancer cell looks promising. Hence, we believe that targeting key protein rRNA methyltransferase FBL shows great potential, due to its pivotal role in ribosome biogenesis, its correlation to an improved survival rate at low expression in breast cancer patients and its association with p53.

KEYWORDS:

Fibrillarin (FBL); Ribosome biogenesis; cancer; chemoresistence; p53; rRNA methyltransferase; ribosomal RNA; therapeutic target; virus.

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