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Review
. 2022 Jan 1;18(3):1211-1219.
doi: 10.7150/ijbs.67529. eCollection 2022.

DNA Replication Licensing Factors: Novel Targets for Cancer Therapy via Inhibiting the Stemness of Cancer Cells

Shaoran Song  1   2 , Yaochun Wang  1   2 , Peijun Liu  1   2
Affiliations
Review

DNA Replication Licensing Factors: Novel Targets for Cancer Therapy via Inhibiting the Stemness of Cancer Cells

Shaoran Song et al. Int J Biol Sci. .

Abstract

The replication licensing factors strictly regulate the DNA replication origin licensing process to guarantee the stability of the genome. Numerous experimental studies have recently demonstrated that the replication licensing factors as oncogenes are essential for the occurrence and development of cancers. Drug resistance, being one of the main characteristics of cancer stem cells, can cause a high recurrence rate and a low survival rate in patients with different cancers. However, the function of the replication licensing factors in cancer stemness remains unclear. The following article highlights the most recent research on DNA replication origin licensing factors in cancer and their function in anti-cancer drug resistance. Moreover, this article proposes a new perspective that replication licensing factors as chemotherapy shield affect anti-cancer drug resistance by promoting the stemness of cancer cells.

Keywords: cancer stem cell; drug resistance; replication initiation factors; stemness.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Five most characteristic properties of CSCs. (1) self-renewal: tumor-sphere formation in vitro/ tumorigenic ability in vivo; (2) the ability of differentiation; (3) the ability of transplantation; (4) resistance of conventional chemotherapy and radiotherapy; (5) unique surface markers.
Figure 2
Figure 2
Brief of DNA replication origin licensing. Sequential loading of replication licensing factors on all potential origins in the genome makes replication initiation restricted to the G1 phase. Firstly, the origin recognition complex (ORC, comprising the six subunits ORC1-6) with ATPase activity is recruited to replication origins, followed by cell division cycle 6 (CDC6) and CDC10-dependent transcript 1 (CDT1) binding to the ORC, and finally the mini-chromosome maintenance helicase complex (MCM2-7) loading into the complex to form Pre-RC.
Figure 3
Figure 3
Inhibition of replication origin licensing factors targeting both cancer cells and CSCs. Since replication licensing factor expression is higher in cancer cells, especially in cancer stem cells, than in normal cells, inhibitors that selectively target replication initiation factors could eradicate both cancer cells and cancer stem cells.
Figure 4
Figure 4
Possible mechanism for targeting Pre-RC to eliminate cancer cells via inhibiting the cancer stemness. Common anti-cancer treatments block one signal transduction pathway to inhibit downstream biological events, including cell proliferation, invasion, and migration. However, cunning tumor cells can trigger cancer recurrence and metastasis by enhancing the transduction of other signaling pathways. Targeting the replication licensing process specifically, which is the foundation for all biological functions, could eradicate cancer thoroughly.
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