Ribosome biogenesis rate, a parameter of sensitivity to chemotherapeutic drugs inhibiting rRNA synthesis

TL;DR

This paper explores how the rate of ribosome biogenesis and genetic changes in ribosomal proteins affect cancer cell sensitivity to drugs that inhibit rRNA synthesis.

Contribution

The paper introduces a framework for predicting cancer cell sensitivity to ribosome biogenesis inhibitors based on ribosome biogenesis rate and ribosomal protein alterations.

Findings

High ribosome biogenesis rates lead to strong MDM2 inhibition and increased cell death in response to ribosome biogenesis inhibitors.

Low ribosome biogenesis rates or ribosomal protein mutations reduce MDM2 inhibition, causing resistance to these drugs.

Combining ribosome biogenesis inhibitors with p53 stabilizers or MDM2 inhibitors can overcome resistance in certain cancer types.

Abstract

Many drugs currently used in cancer chemotherapy exert their toxic action mainly by inhibiting ribosome biogenesis (RiBi). This is due to the fact that after inhibition of rRNA transcription ribosomal proteins, no longer used for ribosome building, bind to and neutralize the activity of the murine double minute 2 protein (MDM2, HMD2 in humans), thus hindering cell proliferation and possibly inducing apoptotic cell death. Here, we discuss the existing literature showing how RiBi rate and genomic alterations of ribosomal proteins (RP mutations/deletions) influence the degree of MDM2 inhibition after treatment with RiBi inhibitors in cancer cells. There is evidence that a high RiBi rate is associated with a high RPs release with strong inhibition of MDM2 activity and consequent induction of apoptotic cell death in response to RiBi inhibitors, whereas a low RiBi rate or RP mutations/deletions are associated with a degree of MDM2 inhibition insufficient to kill cancer cells. In the latter case, in cells with wild type p53, association with drugs which stabilize p53 with different mechanisms may overcome cancer cells resistance to RiBi inhibition, whereas in cancers lacking functional p53 addition of MDM2 inhibitors should be considered. From this, the necessity to evaluate the rate of ribosome biogenesis together with the presence of RP mutations/deletions in cancer tissues for predicting the sensitivity of cancer cells to RiBi inhibitors in order to choose more appropriate therapeutic protocols.

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