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Inhibition of multiple CDKs potentiates colon cancer chemotherapy via p73-mediated DR5 induction

Oncogene volume 42, pages 869–880 (2023)Cite this article

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Abstract

Targeting cyclin-dependent kinases (CDKs) has recently emerged as a promising therapeutic approach against cancer. However, the anticancer mechanisms of different CDK inhibitors (CDKIs) are not well understood. Our recent study revealed that selective CDK4/6 inhibitors sensitize colorectal cancer (CRC) cells to therapy-induced apoptosis by inducing Death Receptor 5 (DR5) via the p53 family member p73. In this study, we investigated if this pathway is involved in anticancer effects of different CDKIs. We found that less-selective CDKIs, including flavopiridol, roscovitine, dinaciclib, and SNS-032, induced DR5 via p73-mediated transcriptional activation. The induction of DR5 by these CDKIs was mediated by dephosphorylation of p73 at Threonine 86 and p73 nuclear translocation. Knockdown of a common target of these CDKIs, including CDK1, 2, or 9, recapitulated p73-mediated DR5 induction. CDKIs strongly synergized with 5-fluorouracil (5-FU), the most commonly used CRC chemotherapy agent, in vitro and in vivo to promote growth suppression and apoptosis, which required DR5 and p73. Together, these findings indicate p73-mediated DR5 induction as a potential tumor suppressive mechanism and a critical target engaged by different CDKIs in potentiating therapy-induced apoptosis in CRC cells. These findings help better understand the anticancer mechanisms of CDKIs and may help facilitate their clinical development and applications in CRC.

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Fig. 1: DR5 induction by CDKIs in CRC cells with different p53 status.
Fig. 2: Transcriptional activation of DR5 by p73 upon CDKI-induced Thr86 dephosphorylation and nuclear translocation.
Fig. 3: Knockdown of CDK1, 2, or 9 recapitulates p73-mediated DR5 induction.
Fig. 4: DR5 is required for apoptosis induced by CDKI/5-FU combinations in CRC cells.
Fig. 5: DR5 mediates apoptosis induced by CDKIs combined with 5-FU via crosstalk of the intrinsic and extrinsic pathways.
Fig. 6: DR5 is required for the in vivo antitumor effects of FVP combined with 5-FU.
Fig. 7: p73 is required for DR5 induction and the in vivo antitumor effects of the FVP/5-FU combination.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

The authors thank our lab members for their discussion and critical reading. This work was supported by the U.S. National Institutes of Health grants (R01CA203028, R01CA217141, R01CA236271, R01CA247231, and R01CA248112 to LZ; R01CA215481 and R01CA260900 to JY; T32GM133332 to KE). This project used the UPMC Hillman Cancer Center Animal Facility, Cytometry Facility, and Tissue and Research Pathology Services, which are supported in part by P30CA047904.

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Authors and Affiliations

  1. UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA

    Jingshan Tong, Xiao Tan, Suisui Hao, Kaylee Ermine, Xinyan Lu, Zhaojin Liu, Anupma Jha, Jian Yu & Lin Zhang

  2. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Jingshan Tong, Xiao Tan, Suisui Hao, Kaylee Ermine, Xinyan Lu, Zhaojin Liu, Anupma Jha & Lin Zhang

  3. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Jian Yu

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JT: experimental design, data acquisition, data analysis, manuscript writing; XT, SH, KE, XL, ZL, AJ: experimental design, data acquisition, data analysis; KE: manuscript editing; JY: funding, supervision, manuscript editing; LZ: funding, supervision, experimental design, data analysis, manuscript writing.

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Correspondence to Lin Zhang.

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Tong, J., Tan, X., Hao, S. et al. Inhibition of multiple CDKs potentiates colon cancer chemotherapy via p73-mediated DR5 induction. Oncogene 42, 869–880 (2023). https://doi.org/10.1038/s41388-023-02598-6

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