Ribosome biogenesis and cancer: basic and translational challenges

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Increasing evidence suggests that alterations in ribosome biogenesis (RiBi) confer competitive advantages to cancer cells. This has led to the discovery of regulatory layers mediated by signaling proteins, oncoproteins, and tumor suppressors whose deregulation leads to increased RiBi rates in cancer cells. In addition to boosting protein synthesis, these alterations probably contribute to shape the protumorigenic proteome of cancer cells. Mutations negatively affecting RiBi are also unexpectedly found in some spontaneous and ribosomopathy-associated tumors. The advantages provided by these genetic lesions to cancer cells remain unsettled as yet. Efforts are being made nowadays to exploit RiBi-associated vulnerabilities and tumor suppressor pathways to design new therapeutic avenues. In this review, we will summarize the main developments and pending challenges in this research area.

Section snippets

Alterations of RiBi pathways in cancer

Mounting evidence has underscored the implication of RiBi in cancer cells. However, the molecular mechanisms that contribute to the deregulation of this process only have begun to be understood in recent years. Perhaps not surprisingly, current findings indicate that one of the most common RiBi regulatory points targeted in cancer cells is the RNA polymerase I (POL I) complex itself. This is a logical interference point since this enzyme is involved in the key rate-limiting step of this

Potential roles of RiBi in cancer

The foregoing data prompt the question of the actual role of RiBi in cancer cells. In the case of RiBi hyperactivity, the most straightforward explanation is that this process favors the increased rates of protein synthesis usually supported by cancer cells. This interpretation is consistent with old findings indicating that translation initiation and elongation factors can facilitate cell transformation (see R. Schneider's review, in this issue). However, it is important to note that the

RiBi-associated therapeutic opportunities

It is widely assumed that RiBi can represent a pharmacologically amenable Achilles’ heel for many tumors, namely those commonly associated with highly increased RiBi rates. This has led to the development of POL I inhibitors with demonstrated antitumor activity such as CX-5461 and BMH-21 [48, 49]. However, it cannot be ruled out that the antitumoral action of these compounds is due to either off-target or indirect effects on POL I. For example, the cytotoxic effects of CX-5461 have recently

Concluding remarks and future perspectives

Despite the progress described above, many lingering problems still remain. One of the main hurdles that preclude further progress in the field is the limited information that still exists on the organization of the RiBi pathway in human cells. Indeed, the molecular details of many steps of the human route, the functions of most human-specific RiBi factors, and the changes that take place in ribosome biogenesis in different cell types, tissues, and physiological conditions remain largely

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors would like to apologize to researchers not cited in this work due to space limitations. Work in XRB lab is supported by grants from the Castilla-León Government (BIO/SA01/15, CSI049U16), the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2015-64556-R, RD12/0036/0002), Worldwide Cancer Research (14-1248), Ramón Areces Foundation, and Spanish Society Against Cancer. Work in MD lab is supported by a MINECO grant (BFU2014-52729-P). Spanish funding is partially cosponsored

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