Abstract
Tumor cells become resistant to structurally or functionally unrelated chemotherapeutics which is called multidrug resistance (MDR). There are several mechanisms including the impairment of apoptotic pathway resulting in MDR development. NEK6 is a member of NIMA-related kinase family and it is an important mitotic kinase for proper cell cycle progression. Recent studies showed that NEK6 gene expression, protein level, and its kinase activity are increased in variety of cancer cells. We aimed to search the involvement of NEK6 in multidrug resistance and apoptosis in chronic myeloid leukemia. The expression levels of NEK6 and some of the apoptotic pathway genes such as BAX, BCL-2 and SURVIVIN were determined in sensitive and drug resistant subtypes of K652 chronic myeloid leukemia cell lines by RT-PCR method. siRNA silencing studies were performed to examine the effect of expression of NEK6 on apoptotic behavior in parental K-562 cell line. Cell viability assay was performed by XTT method in order to investigate whether NEK6 silencing leads to resistance in parental K-562 cells. NEK6 expression is significantly reduced in imatinib resistant K562 cells. After NEK6 gene is silenced by specific siRNA in parental K562 cell line, the expression levels of some apoptotic genes, such as BAX and SURVIVIN were found similar to drug resistant K562 cells. NEK6 may have potential role in imatinib resistance which may be through apoptotic pathway in chronic myeloid leukemia.
Supporting Institution
Middle East Technical University Research Project Foundation
Project Number
BAP-07-02-2014-003
References
- Baran Y, Bielawski J, Gunduz U, Ogretmen B (2011) Targeting glycosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation. J Cancer Res Clin Oncol 137(10):1535-44. doi: 10.1007/s00432-011-1016-y
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- Capra M, Nuciforo PG, Confalonieri S, Quart M, Bianchi M, Nebuloni M, Boldorini R, Pallotti F, Viale G, Gishizky ML, Draetta GF, Di Fioreet PP (2006) Frequent alterations in the expression of serine/threonine kinases in human cancers. Cancer Res 66(16):8147-54. doi: 10.1158/0008-5472.CAN-05-3489
- Fry AM, O’Regan L, Sabir SR, Bayliss R (2012) Cell cycle regulation by the NEK family of protein kinases. J Cell Sci 125(Pt 19):4423-33. doi: 10.1242/jcs.111195
- Jee HJ, Kim AJ, Song N, Kim HJ, Kim M, Koh H, Yun J (2010) Nek6 overexpression antagonizes p53-induced senescence in human cancer cells. Cell Cycle 9(23):4703-10. doi: 10.4161/cc.9.23.14059
- Kars MD, Iseri OD, Gündüz U, Ural AU, Arpaci F, Molnár J (2006) Development of rational in vitro models for drug resistance in breast cancer and modulation of MDR by selected compounds. Anticancer Res 26(6B):4559-68
- Kaufmann SH, Vaux DL (2003) Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene 22(47):7414-30. doi: 10.1038/sj.onc.1206945
- Lee MY, Kim HJ, Kim MA, Hye JJ, Ae JK, Bae YS, Park JI, Chung JH, Yun J (2008) Nek6 is involved in G2/M phase cell cycle arrest through DNA damage-induced phosphorylation. Cell Cycle 7(17):2705-9. doi: 10.4161/cc.7.17.6551
- Moniz L, Dutt P, Haider N,Stambolic V (2011) Nek family of kinases in cell cycle, checkpoint control and cancer. Cell Div 6:18. doi: 10.1186/1747-1028-6-18
- Nassirpour R, Shao L, Flanagan P, Abrams T, Jallal B, Smeal T, Yin M-J (2010) Nek6 mediates human cancer cell transformation and is a potential cancer therapeutic target. Mol Cancer Res 8(5):717-28. doi: 10.1158/1541-7786.MCR-09-0291
- O’Regan L, Fry AM (2009) The Nek6 and Nek7 protein kinases are required for robust mitotic spindle formation and cytokinesis. Mol Cell Biol 29(14):3975-90. doi: 10.1128/MCB.01867-08
- Yin MJ, Shao L, Voehringer D, Smeal T, Jallal B (2003) The serine/threonine kinase Nek6 is required for cell cycle progression through mitosis. J Biol Chem 278(52):52454-60. doi: 10.1074/jbc.M308080200
Abstract
Project Number
BAP-07-02-2014-003
References
- Baran Y, Bielawski J, Gunduz U, Ogretmen B (2011) Targeting glycosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation. J Cancer Res Clin Oncol 137(10):1535-44. doi: 10.1007/s00432-011-1016-y
- Calabretta B, Perrotti D. The biology of CML blast crisis (2004) Blood 103(11):4010-22. doi: 10.1182/blood-2003-12-4111
- Capra M, Nuciforo PG, Confalonieri S, Quart M, Bianchi M, Nebuloni M, Boldorini R, Pallotti F, Viale G, Gishizky ML, Draetta GF, Di Fioreet PP (2006) Frequent alterations in the expression of serine/threonine kinases in human cancers. Cancer Res 66(16):8147-54. doi: 10.1158/0008-5472.CAN-05-3489
- Fry AM, O’Regan L, Sabir SR, Bayliss R (2012) Cell cycle regulation by the NEK family of protein kinases. J Cell Sci 125(Pt 19):4423-33. doi: 10.1242/jcs.111195
- Jee HJ, Kim AJ, Song N, Kim HJ, Kim M, Koh H, Yun J (2010) Nek6 overexpression antagonizes p53-induced senescence in human cancer cells. Cell Cycle 9(23):4703-10. doi: 10.4161/cc.9.23.14059
- Kars MD, Iseri OD, Gündüz U, Ural AU, Arpaci F, Molnár J (2006) Development of rational in vitro models for drug resistance in breast cancer and modulation of MDR by selected compounds. Anticancer Res 26(6B):4559-68
- Kaufmann SH, Vaux DL (2003) Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene 22(47):7414-30. doi: 10.1038/sj.onc.1206945
- Lee MY, Kim HJ, Kim MA, Hye JJ, Ae JK, Bae YS, Park JI, Chung JH, Yun J (2008) Nek6 is involved in G2/M phase cell cycle arrest through DNA damage-induced phosphorylation. Cell Cycle 7(17):2705-9. doi: 10.4161/cc.7.17.6551
- Moniz L, Dutt P, Haider N,Stambolic V (2011) Nek family of kinases in cell cycle, checkpoint control and cancer. Cell Div 6:18. doi: 10.1186/1747-1028-6-18
- Nassirpour R, Shao L, Flanagan P, Abrams T, Jallal B, Smeal T, Yin M-J (2010) Nek6 mediates human cancer cell transformation and is a potential cancer therapeutic target. Mol Cancer Res 8(5):717-28. doi: 10.1158/1541-7786.MCR-09-0291
- O’Regan L, Fry AM (2009) The Nek6 and Nek7 protein kinases are required for robust mitotic spindle formation and cytokinesis. Mol Cell Biol 29(14):3975-90. doi: 10.1128/MCB.01867-08
- Yin MJ, Shao L, Voehringer D, Smeal T, Jallal B (2003) The serine/threonine kinase Nek6 is required for cell cycle progression through mitosis. J Biol Chem 278(52):52454-60. doi: 10.1074/jbc.M308080200
Details
| Primary Language | English |
|---|---|
| Subjects | Clinical Chemistry |
| Journal Section | Research Articles |
| Authors | |
| Project Number | BAP-07-02-2014-003 |
| Publication Date | June 21, 2022 |
| Acceptance Date | April 28, 2022 |
| Published in Issue | Year 2022 |