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Selective CDK9 knockdown sensitizes TRAIL response by suppression of antiapoptotic factors and NF-kappaB pathway

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Abstract

The aberrantly up-regulated CDK9 can be targeted for cancer therapy. The CDK inhibitor dinaciclib (Dina) has been found to drastically sensitizes cancer response to TRAIL-expressing extracellular vesicle (EV-T). However, the low selectivity of Dina has limited its application for cancer. We propose that CDK9-targeted siRNA (siCDK9) may be a good alternative to Dina. The siCDK9 molecules were encapsulated into EV-Ts to prepare a complexed nanodrug (siEV-T). It was shown to efficiently suppress CDK9 expression and overcome TRAIL resistance to induce strikingly augmented apoptosis in lung cancer both in vitro and in vivo, with a mechanism related to suppression of both anti-apoptotic factors and nuclear factor-kappa B pathway. Therefore, siEV-T potentially constitutes a novel, highly effective and safe therapy for cancers.

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References

  1. Kumar SK et al (2015) Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood 125(3):443–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hortobagyi GN et al (2016) Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 375(18):1738–1748

    Article  CAS  PubMed  Google Scholar 

  3. Serra F et al (2019) Palbociclib in metastatic breast cancer: current evidence and real-life data. Drugs Context 8:212579

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wang Y, Liu XY, De Clercq E (2009) Role of the HIV-1 positive elongation factor P-TEFb and inhibitors thereof. Mini Rev Med Chem 9(3):379–385

    Article  CAS  PubMed  Google Scholar 

  5. Mandal R, Becker S, Strebhardt K (2021) Targeting CDK9 for anti-cancer therapeutics. Cancers (Basel) 13:9

    Article  Google Scholar 

  6. Abdalla Y et al (2021) Safranal prevents liver cancer through inhibiting oxidative stress and alleviating inflammation. Front Pharmacol 12:777500

    Article  CAS  PubMed  Google Scholar 

  7. Amin A et al (2011) Pancreas-protective effects of chlorella in STZ-induced diabetic animal model: insights into the mechanism. J Diabet Mell 1(3):36–45

    Article  Google Scholar 

  8. El-Dakhly SM et al (2020) Aescin and diosmin each alone or in low dose- combination ameliorate liver damage induced by carbon tetrachloride in rats. BMC Res Notes 13(1):259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Abdel-Latif R et al (2022) TLRs-JNK/ NF-κB pathway underlies the protective effect of the sulfide salt against liver toxicity. Front Pharmacol 13:850066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ke C et al (2020) Extracellular vesicle delivery of TRAIL eradicates resistant tumor growth in combination with CDK inhibition by dinaciclib. Cancers (Basel) 12:5

    Article  Google Scholar 

  11. Lemke J et al (2014) Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1. Cell Death Differ 21(3):491–502

    Article  CAS  PubMed  Google Scholar 

  12. Wang HK (2001) Flavopiridol. National cancer institute. Curr Opin Investig Drugs 2(8):1149–1155

    CAS  PubMed  Google Scholar 

  13. Blachly JS, Byrd JC (2013) Emerging drug profile: cyclin-dependent kinase inhibitors. Leuk Lymphoma 54(10):2133–2143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Anshabo AT et al (2021) CDK9: a comprehensive review of its biology, and its role as a potential target for anti-cancer agents. Front Oncol 11:678559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gojo I et al (2013) Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias. Cancer Chemother Pharmacol 72(4):897–908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fabre C et al (2014) Clinical study of the novel cyclin-dependent kinase inhibitor dinaciclib in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia patients. Cancer Chemother Pharmacol 74(5):1057–1064

    Article  CAS  PubMed  Google Scholar 

  17. Parry D et al (2010) Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther 9(8):2344–2353

    Article  CAS  PubMed  Google Scholar 

  18. Crean S et al (2009) Safety of multi-targeted kinase inhibitors as monotherapy treatment of cancer: a systematic review of the literature. Curr Drug Saf 4(2):143–154

    Article  PubMed  Google Scholar 

  19. Goel B et al (2020) Small molecule CDK inhibitors for the therapeutic management of cancer. Curr Top Med Chem 20(17):1535–1563

    Article  CAS  PubMed  Google Scholar 

  20. Saw PE, Song EW (2020) siRNA therapeutics: a clinical reality. Sci China Life Sci 63(4):485–500

    Article  CAS  PubMed  Google Scholar 

  21. Kaur K et al (2018) Chemotherapy with si-RNA and anti-cancer drugs. Curr Drug Deliv 15(3):300–311

    Article  CAS  PubMed  Google Scholar 

  22. Mendt M et al (2018) Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 3:8

    Article  Google Scholar 

  23. Hou H et al (2021) TRAIL-Armed ER nanosomes induce drastically enhanced apoptosis in resistant tumor in combination with the antagonist of IAPs (AZD5582). Adv Healthc Mater 10(11):e2100030

    Article  PubMed  Google Scholar 

  24. Ke C et al (2022) Extracellular vesicle-mediated co-delivery of TRAIL and dinaciclib for targeted therapy of resistant tumors. Biomater Sci 10(6):1498–1514

    Article  CAS  PubMed  Google Scholar 

  25. Higginbotham JN et al (2016) Identification and characterization of EGF receptor in individual exosomes by fluorescence-activated vesicle sorting. J Extracell Vesicles 5:29254

    Article  PubMed  Google Scholar 

  26. Ke C et al (2020) Extracellular vesicle delivery of TRAIL eradicates resistant tumor growth in combination with CDK inhibition by dinaciclib. Cancers 12:5

    Article  Google Scholar 

  27. Levy JMM, Towers CG, Thorburn A (2017) Targeting autophagy in cancer. Nat Rev Cancer 17(9):528–542

    Article  CAS  PubMed  Google Scholar 

  28. Deng D, Shah K (2020) TRAIL of hope meeting resistance in cancer. Trends Cancer 6(12):989–1001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yuan Z et al (2015) Mesenchymal stromal cell delivery of full-length tumor necrosis factor-related apoptosis-inducing ligand is superior to soluble type for cancer therapy. Cytotherapy 17(7):885–896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Huang C et al (2022) Sensitizing TRAIL response via differential modulation of anti- and pro-apoptotic factors by AZD5582 combined with ER nanosomal TRAIL in neuroblastoma. Acta Histochem 124(2):151856

    Article  CAS  PubMed  Google Scholar 

  31. Paparidis NF, Durvale MC, Canduri F (2017) The emerging picture of CDK9/P-TEFb: more than 20 years of advances since PITALRE. Mol Biosyst 13(2):246–276

    Article  PubMed  Google Scholar 

  32. He S et al (2020) Targeting CDK9: a novel biomarker in the treatment of endometrial cancer. Oncol Rep 44(5):1929–1938

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Sengupta S, Biarnes MC, Jordan VC (2014) Cyclin dependent kinase-9 mediated transcriptional de-regulation of cMYC as a critical determinant of endocrine-therapy resistance in breast cancers. Breast Cancer Res Treat 143(1):113–124

    Article  CAS  PubMed  Google Scholar 

  34. Maguire O, O’Loughlin K, Minderman H (2015) Simultaneous assessment of NF-κB/p65 phosphorylation and nuclear localization using imaging flow cytometry. J Immunol Methods 423:3–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260

    Article  CAS  PubMed  Google Scholar 

  36. Tilborghs S et al (2017) The role of Nuclear Factor-kappa B signaling in human cervical cancer. Crit Rev Oncol Hematol 120:141–150

    Article  PubMed  Google Scholar 

  37. Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5(10):749–759

    Article  CAS  PubMed  Google Scholar 

  38. Peng C et al (2020) The NF-κB signaling pathway, the microbiota, and gastrointestinal tumorigenesis: recent advances. Front Immunol 11:1387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rasmi RR, Sakthivel KM, Guruvayoorappan C (2020) NF-κB inhibitors in treatment and prevention of lung cancer. Biomed Pharmacother 130:110569

    Article  CAS  PubMed  Google Scholar 

  40. Baldwin AS (2012) Regulation of cell death and autophagy by IKK and NF-κB: critical mechanisms in immune function and cancer. Immunol Rev 246(1):327–345

    Article  PubMed  Google Scholar 

  41. Katsman A, Umezawa K, Bonavida B (2009) Chemosensitization and immunosensitization of resistant cancer cells to apoptosis and inhibition of metastasis by the specific NF-kappaB inhibitor DHMEQ. Curr Pharm Des 15(7):792–808

    Article  CAS  PubMed  Google Scholar 

  42. Mi J et al (2007) NF-kappaB inhibition by an adenovirus expressed aptamer sensitizes TNFalpha-induced apoptosis. Biochem Biophys Res Commun 359(3):475–480

    Article  CAS  PubMed  Google Scholar 

  43. D’Arcy MS (2019) Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 43(6):582–592

    Article  PubMed  Google Scholar 

  44. Fan H et al (2022) Carbon nanoparticles induce DNA repair and PARP inhibitor resistance associated with nanozyme activity in cancer cells. Cancer Nanotechnology 13:1

    Article  CAS  Google Scholar 

  45. Al Hrout A et al (2022) Modelling liver cancer microenvironment using a novel 3D culture system. Sci Rep 12(1):8003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nelson DR et al (2022) Molecular mechanisms behind safranal’s toxicity to HepG2 cells from dual omics. Antioxidants (Basel) 11:6

    Google Scholar 

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Funding

Z.Q.Y. is a China Talented Scholar Scheme Research Fellow in the School of Biomedical and Pharmaceutical Sciences and is supported by National Natural Science Foundation of China (grant number 82173850), the University Innovative Team Support for Major Chronic Diseases and Drug Development (26330320901), and the Guangdong Provincial Talented Scholar Foundation (220418137).

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Author notes

  1. Qian Yuan, Kui Su and Shuyi Li equally contributed to this work.

Authors and Affiliations

  1. School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, People’s Republic of China

    Qian Yuan, Kui Su, Shuyi Li, Xinyi Long, Lang Liu, Jianwu Sun, Xin Yuan, Minghui Yang, Rui Tian, Wanting Zhang, Zhujie Deng, Quanjiang Li, Changhong Ke, Wei Zhou & Zhengqiang Yuan

  2. Jinhang Bio-Science and Biotechnology Co. Ltd, Guangzhou, 510630, People’s Republic of China

    Yue He, Chunming Cheng, Jingna Yuan & Zhuohao Wen

Authors
  1. Qian Yuan
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  18. Wei Zhou
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Contributions

Q.Y., K.S., and S.Y.L. contributed equally to this work. Conceptualization, Q.Y., K.S., S.Y.L., and Z.Q.Y.; methodology, Q.Y.,K.S., X.Y.L., L.L.,C.H.K., W.J.S., Y.H., R.T., W.T.Z., Z.J.D., C.M.C., Q.J.L., J.N.Y., Z.H.W., formal analysis, Z.Q.Y., Q.Y., C.H.K., and M.H.Y.,; investigation, Q.Y., X.Y., W.Z.; resources, Z.Q.Y.,; writing-original draft preparation, Q.Y., and Z.Q.Y.; Funding Acquisition, Z.Q.Y.

Corresponding authors

Correspondence to Wei Zhou or Zhengqiang Yuan.

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The authors declare no competing interests.

Ethical approval

All procedures and protocols for in vivo study were approved by the Animal Ethics Committee in South China University of Technology (Approval ID: 20221020239; Date: February 2, 2022). All animal model experiments were carried out in accordance with the ethical standards outlined in the Best Practice Guidelines on Publishing Ethics.

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Yuan, Q., Su, K., Li, S. et al. Selective CDK9 knockdown sensitizes TRAIL response by suppression of antiapoptotic factors and NF-kappaB pathway. Apoptosis 28, 1060–1075 (2023). https://doi.org/10.1007/s10495-023-01842-4

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