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KNK437 restricts the growth and metastasis of colorectal cancer via targeting DNAJA1/CDC45 axis

Oncogene volume 39, pages 249–261 (2020)Cite this article

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Abstract

As an inhibitor of heat shock proteins (HSPs), KNK437 has been reported to play an anti-tumor role in several cancers. But its therapeutic effect and mechanisms in colorectal cancer (CRC) remain unclear. Here, KNK437 sharply inhibited the level of DnaJ heat shock protein family (Hsp40) member A1 (DNAJA1), followed by DNAJB1, but had little effect on the levels of HSP27, HSP105, HSP90, and HSP70 in CRC cells. DNAJA1 promoted CRC cell proliferation in vitro and tumor growth and metastasis in vivo. Mechanistically, DNAJA1 was activated by E2F transcription factor 1 (E2F1) and then promoted cell cycle by stabilizing cell division cycle protein 45 (CDC45), which could be reversed by KNK437. DNAJA1 was significantly upregulated in CRC tissues and positively correlated with serosa invasion, lymph node metastasis. High level of DNAJA1 predicted poor prognosis for CRC patients. Its expression was highly linked with E2F1 and CDC45 in CRC tissues. More importantly, KNK437 significantly suppressed the growth of DNAJA1 expressing tumor in vivo. The combined treatment of KNK437 with 5-FU/L-OHP chemotherapy reduced liver metastasis of CRC. These data reveal a novel mechanism of KNK437 in anti-tumor therapy of CRC and provides a newly therapeutic strategy with potential translation to the CRC patients.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

    PubMed  Google Scholar 

  2. Jaattela M. Heat shock proteins as cellular lifeguards. Ann Med. 1999;31:261–71.

    CAS  PubMed  Google Scholar 

  3. Matijasevic Z, Snyder JE, Ludlum DB. Hypothermia causes a reversible, p53-mediated cell cycle arrest in cultured fibroblasts. Oncol Res. 1998;10:605–10.

    CAS  PubMed  Google Scholar 

  4. Sonna LA, Fujita J, Gaffin SL, Lilly CM. Effects of heat and cold stress on mammalian gene expression. J Appl Physiol. 2002;92:1725–42.

    CAS  PubMed  Google Scholar 

  5. Haggerty TJ, Dunn IS, Rose LB, Newton EE, Pandolfi F, Kurnick JT. Heat shock protein-90 inhibitors enhance antigen expression on melanomas and increase T cell recognition of tumor cells. PLoS ONE. 2014;12:e114506.

    Google Scholar 

  6. Bodoor K, Jalboush SA, Matalka I, Abu-Sheikha A, Waq RA, Ebwaini H, et al. Heat shock protein association with clinico-pathological characteristics of gastric cancer in Jordan: HSP70 is predictive of poor prognosis. Asian Pac J Cancer Prev. 2016;17:3929–37.

    PubMed  Google Scholar 

  7. Thorsteinsdottir J, Stangl S, Fu P, Guo K, Albrecht V, Eigenbrod S, et al. Overexpression of cytosolic, plasma membrane bound and extracellular heat shock protein 70 (Hsp70) in primary glioblastomas. J Neurooncol. 2017;135:443–52.

    CAS  PubMed  Google Scholar 

  8. Jagadish N, Agarwal S, Gupta N, Fatima R, Devi S, Kumar V, et al. Heat shock protein 70-2 (HSP70-2) overexpression in breast cancer. J Exp Clin Cancer Res. 2016;35:150.

    PubMed  PubMed Central  Google Scholar 

  9. Jhaveri K, Wang R, Teplinsky E, Chandarlapaty S, Solit D, Cadoo K, et al. A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer. Breast Cancer Res. 2017;19:89.

    PubMed  PubMed Central  Google Scholar 

  10. Wang Y, Liu H, Diao L, Potter A, Zhang J, Qiao Y, et al. Hsp90 inhibitor ganetespib sensitizes non-small cell lung cancer to radiation but has variable effects with chemoradiation. Clin Cancer Res. 2016;22:5876–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lee HG, Park WJ, Shin SJ, Kwon SH, Cha SD, Seo YH, et al. Hsp90 inhibitor SY-016 induces G2/M arrest and apoptosis in paclitaxel-resistant human ovarian cancer cells. Oncol Lett. 2017;13:2817–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Ramalingam S, Goss G, Rosell R, Schmid-Bindert G, Zaric B, Andric Z, et al. A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1). Ann Oncol. 2015;26:1741–8.

    CAS  PubMed  Google Scholar 

  13. Ban HS, Naik R, Kim HM, Kim BK, Lee H, Kim I, et al. Identification of targets of the HIF-1 Inhibitor IDF-11774 using alkyne-conjugated photoaffinity probes. Bioconjugugate Chem. 2016;27:1911–20.

    CAS  Google Scholar 

  14. Taba K, Kuramitsu Y, Ryozawa S, Yoshida K, Tanaka T, Mori-Iwamoto S, et al. KNK437 downregulates heat shock protein 27 of pancreatic cancer cells and enhances the cytotoxic effect of gemcitabine. Chemotherapy. 2011;57:12–6.

    CAS  PubMed  Google Scholar 

  15. Sahin E, Sahin M, Sanlioğlu AD, Gümüslü S. KNK437, a benzylidene lactam compound, sensitises prostate cancer cells to the apoptotic effect of hyperthermia. Int J Hyperth. 2011;27:63–73.

    CAS  Google Scholar 

  16. Yokota S, Kitahara M, Nagata K. Benzylidene lactam compound, KNK437, a novel inhibitor of acquisition of thermotolerance and heat shock protein induction in human colon carcinoma cells. Cancer Res. 2000;60:2942–8.

    CAS  PubMed  Google Scholar 

  17. Terada K, Yomogida K, Imai T, Kiyonari H, Takeda N, Kadomatsu T, et al. A type I DnaJ homolog, DjA1, regulates androgen receptor signaling and spermatogenesis. EMBO J. 2005;24:611–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang CC, Liao YP, Mischel PS, Iwamoto KS, Cacalano NA, McBride WH. HDJ-2 as a target for radiosensitization of glioblastoma multiforme cells by the farnesyltransferase inhibitor R115777 and the role of the p53/p21 pathway. Cancer Res. 2006;66:6756–62.

    CAS  PubMed  Google Scholar 

  19. Stark JL, Mehla K, Chaika N, Acton TB, Xiao R, Singh PK, et al. Structure and function of human DnaJ homologue subfamily a member 1 (DNAJA1) and its relationship to pancreatic cancer. Biochemistry. 2014;53:1360–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Banerji U, O’Donnell A, Scurr M, Pacey S, Stapleton S, Asad Y, et al. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygel- danamycin in patients with advanced malignancies. J Clin Oncol. 2005;23:4152–61.

    CAS  PubMed  Google Scholar 

  21. Hadchity E, Aloy MT, Paulin C, Armandy E, Watkin E, Rousson R, et al. Heat shock protein 27 as a new therapeutic target for radiation sensitization of head and neck squamous cell carcinoma. Mol Ther. 2009;17:1387–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kudryavtsev VA, Khokhlova AV, Mosina VA, Selivanova EI, Kabakov AE. Induction of Hsp70 in tumor cells treated with inhibitors of the Hsp90 activity: a predictive marker and promising target for radiosensitization. PLoS ONE. 2017;12:e0173640.

    PubMed  PubMed Central  Google Scholar 

  23. Kimura A, Ogata K, Altan B, Yokobori T, Mochiki E, Yanai M, et al. Nuclear heat shock protein 110 expression is associated with poor prognosis and hyperthermo-chemotherapy resistance in gastric cancer patients with peritoneal metastasis. World J Gastroenterol. 2017;23:7541–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kuramitsu Y, Wang Y, Taba K, Suenaga S, Ryozawa S, Kaino S, et al. Heat-shock protein 27 plays the key role in gemcitabine-resistance of pancreatic cancer cells. Anticancer Res. 2012;32:2295–9.

    CAS  PubMed  Google Scholar 

  25. Oommen D, Prise KM. KNK437, abrogates hypoxia-induced radioresistance by dual targeting of the AKT and HIF-1α survival pathways. Biochem Biophys Res Commun. 2012;421:538–43.

    CAS  PubMed  Google Scholar 

  26. Barrio S, Gallardo M, Arenas A, Ayala R, Rapado I, Rueda D, et al. Inhibition of related JAK/STAT pathways with molecular targeted drugs shows strong synergy with ruxolitinib in chronic myeloproliferative neoplasm. Br J Haematol. 2013;161:667–76.

    CAS  PubMed  Google Scholar 

  27. Qiu XB, Shao YM, Miao S, Wang L. The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones. Cell Mol Life Sci. 2006;63:2560–70.

    CAS  PubMed  Google Scholar 

  28. Walsh P, Bursać D, Law YC, Cyr D, Lithgow T. The J-protein family: modulating protein assembly, disassembly and translocation. EMBO Rep. 2004;5:567–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kotlarz A, Tukaj S, Krzewski K, Brycka E, Lipinska B. Human Hsp40 proteins, DNAJA1 and DNAJA2, as potential targets of the immune response triggered by bacterial DnaJ in rheumatoid arthritis. Cell Stress Chaperon-. 2013;18:653–9.

    CAS  Google Scholar 

  30. Gibbs SJ, Braun JE. Emerging roles of J proteins in neurodegenerative disorders. Neurobiol Dis. 2008;32:196–9.

    CAS  PubMed  Google Scholar 

  31. Meshalkina DA, Shevtsov MA, Dobrodumov AV, Komarova EY, Voronkina IV, Lazarev VF, et al. Knock-down of Hdj2/DNAJA1 co-chaperone results in an unexpected burst of tumorigenicity of C6 glioblastoma cells. Oncotarget. 2016;7:22050–63.

    PubMed  PubMed Central  Google Scholar 

  32. Chen HZ, Tsai SY, Leone G. Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer. 2009;9:785–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Tanaka H, Matsumura I, Ezoe S, Satoh Y, Sakamaki T, Albanese C, et al. E2F1 and c-Myc potentiate apoptosis through inhibition of NF-kappaB activity that facilitates MnSOD-mediated ROS elimination. Mol Cell. 2002;9:1017–29.

    CAS  PubMed  Google Scholar 

  34. Bracken AP, Ciro M, Cocito A, Helin K. E2F target genes: unraveling the biology. Trends Biochem. 2004;29:409–17.

    CAS  Google Scholar 

  35. Ohtani K, DeGregori J, Nevins JR. Regulation of the cyclin E gene by transcription factor E2F1. Proc Natl Acad Sci USA. 1995;92:12146–50.

    CAS  PubMed  Google Scholar 

  36. Bauerschmidt C, Pollok S, Kremmer E, Nasheuer HP, Grosse F. Interactions of human Cdc45 with the Mcm2-7 complex, the GINS complex, and DNA polymerases delta and epsilon during S phase. Genes Cells. 2007;12:745–58.

    CAS  PubMed  Google Scholar 

  37. Hardy CF. Identification of Cdc45p, an essential factor required for DNA replication. Gene. 1997;187:239–46.

    CAS  PubMed  Google Scholar 

  38. Nasheuer HP, Smith R, Bauerschmidt C, Grosse F, Weisshart K. Initiation of eukaryotic DNA replication: regulation and mechanisms. Prog Nucleic Acid Res Mol Biol. 2002;72:41–94.

    CAS  PubMed  Google Scholar 

  39. Sun J, Shi R, Zhao S, Li X, Lu S, Bu H, et al. Cell division cycle 45 promotes papillary thyroid cancer progression via regulating cell cycle. Tumour Biol. 2017;39:1010428317705342.

    PubMed  Google Scholar 

  40. Li HY, Jin N, Han YP, Jin XF. Pathway crosstalk analysis in prostate cancer based on protein-protein network data. Neoplasma. 2017;64:22–31.

    CAS  PubMed  Google Scholar 

  41. Tane S, Sakai Y, Hokka D, Okuma H, Ogawa H, Tanaka Y, et al. Significant role of Psf3 expression in non-small-cell lung cancer. Cancer Sci. 2015;106:1625–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Haider S, Jun W, Nagano A, Desai A, Arumugam P, Dumartin L, et al. A multi-gene signature predicts outcome in patients with pancreatic ductal adenocarcinoma. Genome Med. 2014;6:105.

    PubMed  PubMed Central  Google Scholar 

  43. Parrales A, Ranjan A, Iyer SV, Padhye S, Weir SJ. DNAJA1 controls the fate of misfoldedmutant p53 through the mevalonate pathway. Nat Cell Biol. 2016;18:1233–43.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National key R&D program of China (2017YFC1309002), National Basic Research Program of China (973 Program, 2015CB554002), National Natural Science Foundation of China (81672821, 81472313, 81773101, 81272759, 81401927, 81302151, and 81802306), Project funded by China Postdoctoral Science Foundation (2018M633081 and 2018M633079), Natural Science Foundation of Guangdong Province (2018A030310457).

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  1. These authors contributed equally: Shaoshan Yang, Xiaoli Ren, Yunshi Liang, Yongrong Yan

Authors and Affiliations

  1. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, People’s Republic of China

    Shaoshan Yang, Xiaoli Ren, Yunshi Liang, Yongrong Yan, Yangshu Zhou, Jinlong Hu, Zhizhi Wang, Fuyao Song, Feifei Wang, Wenting Liao, Yanqing Ding & Li Liang

  2. Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong Province, People’s Republic of China

    Shaoshan Yang, Xiaoli Ren, Yunshi Liang, Yongrong Yan, Yangshu Zhou, Jinlong Hu, Zhizhi Wang, Fuyao Song, Feifei Wang, Wenting Liao, Yanqing Ding & Li Liang

  3. Department of Pathology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong Province, People’s Republic of China

    Shaoshan Yang

  4. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, People’s Republic of China

    Wangjun Liao

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Yang, S., Ren, X., Liang, Y. et al. KNK437 restricts the growth and metastasis of colorectal cancer via targeting DNAJA1/CDC45 axis. Oncogene 39, 249–261 (2020). https://doi.org/10.1038/s41388-019-0978-0

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