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RETRACTED ARTICLE: Cabozantinib induces PUMA-dependent apoptosis in colon cancer cells via AKT/GSK-3β/NF-κB signaling pathway

Cancer Gene Therapy volume 27, pages 368–377 (2020)Cite this article

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This article was retracted on 14 October 2022

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Abstract

Cabozantinib is a multi-kinase inhibitor targeting MET, AXL, and VEGFR2, and has been approved for use in multiple malignancies. The means by which Cabozantinib acts to target colorectal cancer (CRC) cells remains poorly understood, and we sought to investigate how this drug disrupts cell growth in CRC cells and how it interacts to enhance the efficacy of other chemotherapeutic agents. In this study, we found that Cabozantinib activated a p65-dependent signaling pathway in response to both inhibition of AKT and activation of glycogen synthase kinase 3β (GSK3β), leading to upregulation of PUMA in CRC cells regardless of p53 activity. PUMA upregulation facilitates CRC apoptosis in response to Cabozantinib, which also acts synergistically with the chemotherapeutic agents Cetuximab and 5-FU to induce robust apoptosis in a PUMA-dependent manner. Eliminating PUMA expression ablated this apoptosis induced by Cabozantinib in xenograft mouse model. Our findings revealed that Cabozantinib acts to drive CRC cells apoptosis via a PUMA-dependent mechanism, thus identifying PUMA expression as a potential predictor of Cabozantinib efficacy and a potential novel therapeutic target.

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References

  1. Lee SJ, Yun CC. Colorectal cancer cells—proliferation, survival and invasion by lysophosphatidic acid. Int J Biochem Cell Biol. 2010;42:1907–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tong J, Zheng X, Tan X, Fletcher R, Nikolovska-Coleska Z, Yu J, et al. Mcl-1 phosphorylation without degradation mediates sensitivity to HDAC inhibitors by liberating BH3-only proteins. Cancer Res. 2018;78:4704–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Szarynska M, Olejniczak A, Kobiela J, Spychalski P, Kmiec Z. Therapeutic strategies against cancer stem cells in human colorectal cancer. Oncol Lett. 2017;14:7653–68.

    PubMed  PubMed Central  Google Scholar 

  4. Guglielmo A, Staropoli N, Giancotti M, Mauro M. Personalized medicine in colorectal cancer diagnosis and treatment: a systematic review of health economic evaluations. Cost Eff Resour Alloc. 2018;16:2.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Knickelbein K, Tong J, Chen D, Wang YJ, Misale S, Bardelli A, et al. Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer. Oncogene. 2018;37:4599–610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen D, Tong J, Yang L, Wei L, Stolz DB, Yu J, et al. PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors. Proc Natl Acad Sci USA. 2018;115:3930–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Blanco-Calvo M, Concha A, Figueroa A, Garrido F, Valladares-Ayerbes M. Colorectal cancer classification and cell heterogeneity: a systems oncology approach. Int J Mol Sci. 2015;16:13610–32.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Blank A, Roberts DE 2nd, Dawson H, Zlobec I, Lugli A. Tumor heterogeneity in primary colorectal cancer and corresponding metastases. Does the apple fall far from the tree? Front Med. 2018;5:234.

    Article  Google Scholar 

  9. Testa U, Pelosi E, Castelli G Colorectal cancer: genetic abnormalities, tumor progression, tumor heterogeneity, clonal evolution and tumor-initiating cells. Med Sci 2018;6:31–144.

  10. Lacy SA, Miles DR, Nguyen LT. Clinical pharmacokinetics and pharmacodynamics of cabozantinib. Clin Pharm. 2017;56:477–91.

    Article  Google Scholar 

  11. ML BP, Miksad RA. Cabozantinib in the treatment of hepatocellular carcinoma. Future Oncol 2017;13:1915–29.

  12. Pathi SS, Lei P, Sreevalsan S, Chadalapaka G, Jutooru I, Safe S. Pharmacologic doses of ascorbic acid repress specificity protein (Sp) transcription factors and Sp-regulated genes in colon cancer cells. Nutr Cancer. 2011;63:1133–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Matsumoto K, Umitsu M, De Silva DM, Roy A, Bottaro DP. Hepatocyte growth factor/MET in cancer progression and biomarker discovery. Cancer Sci. 2017;108:296–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tong J, Tan S, Zou F, Yu J, Zhang L. FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation. Oncogene. 2017;36:787–96.

    Article  CAS  PubMed  Google Scholar 

  15. He K, Chen D, Ruan H, Li X, Tong J, Xu X, et al. BRAFV600E-dependent Mcl-1 stabilization leads to everolimus resistance in colon cancer cells. Oncotarget. 2016;7:47699–710.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tong J, Tan S, Nikolovska-Coleska Z, Yu J, Zou F, Zhang L. FBW7-dependent Mcl-1 degradation mediates the anticancer effect of Hsp90 inhibitors. Mol Cancer Ther. 2017;16:1979–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tong J, Wang P, Tan S, Chen D, Nikolovska-Coleska Z, Zou F, et al. Mcl-1 degradation is required for targeted therapeutics to eradicate colon cancer cells. Cancer Res. 2017;77:2512–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Truffaux N, Philippe C, Paulsson J, Andreiuolo F, Guerrini-Rousseau L, Cornilleau G, et al. Preclinical evaluation of dasatinib alone and in combination with cabozantinib for the treatment of diffuse intrinsic pontine glioma. Neuro Oncol. 2015;17:953–64.

    Article  CAS  PubMed  Google Scholar 

  19. Zhen DB, Griffith KA, Ruch JM, Camphausen K, Savage JE, Kim EJ, et al. A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer. Invest New Drugs. 2016;34:733–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang Q, Tian K, Xu J, Zhang H, Li L, Fu Q, et al. Synergistic effects of cabozantinib and EGFR-Specific CAR-NK-92 cells in renal cell carcinoma. J Immunol Res. 2017;2017:6915912.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chang JW, Kang SU, Shin YS, Seo SJ, Kim YS, Yang SS, et al. Combination of NTP with cetuximab inhibited invasion/migration of cetuximab-resistant OSCC cells: involvement of NF-kappaB signaling. Sci Rep. 2015;5:18208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zuo Q, Shi M, Chen J, Liao W. The Ras signaling pathway mediates cetuximab resistance in nasopharyngeal carcinoma. Biomed Pharm. 2011;65:168–74.

    Article  CAS  Google Scholar 

  23. Sun Q, Ming L, Thomas SM, Wang Y, Chen ZG, Ferris RL, et al. PUMA mediates EGFR tyrosine kinase inhibitor-induced apoptosis in head and neck cancer cells. Oncogene. 2009;28:2348–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sun Q, Lesperance J, Wettersten H, Luterstein E, DeRose YS, Welm A, et al. Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis. J Clin Invest. 2018;128:531–44.

    Article  PubMed  Google Scholar 

  25. Wang A, Wang W, Chen Y, Ma F, Wei X, Bi Y. Deguelin induces PUMA-mediated apoptosis and promotes sensitivity of lung cancer cells (LCCs) to doxorubicin (Dox). Mol Cell Biochem. 2018;442:177–86.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by Natural Science Foundation of Liaoning (No. 20180550877 to Shida Yang and No. 20180550530 to Huiling Qu).

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Author notes

  1. These authors contributed equally: Shida Yang, Xiaobing Zhang, Huiling Qu

Authors and Affiliations

  1. Department of Laboratory Medicine, The people’s Hospital of Liaoning Province, Shenyang, China

    Shida Yang, Xiaobing Zhang, Bo Qu, Xiaoxue Yin & Hongmei Zhao

  2. Department of Neurology, The people’s Hospital of Liaoning Province, Shenyang, China

    Huiling Qu

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  1. Shida Yang
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Correspondence to Hongmei Zhao.

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This article has been retracted. Please see the retraction notice for more detail: https://doi.org/10.1038/s41417-022-00545-3

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Yang, S., Zhang, X., Qu, H. et al. RETRACTED ARTICLE: Cabozantinib induces PUMA-dependent apoptosis in colon cancer cells via AKT/GSK-3β/NF-κB signaling pathway. Cancer Gene Ther 27, 368–377 (2020). https://doi.org/10.1038/s41417-019-0098-6

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