Investigation of the role of programmed cell death 10 (PDCD10) protein in multidrug resistance

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2018

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Urfalı Mamatoğlu, Çağrı

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Drug resistance, a major obstacle in chemotherapy, is the sum of several cellular alterations including resistance to induction of apoptosis. Apoptosis is a well-regulated cell death mechanism which is controlled by several signaling pathways and a vast number of proteins. Alterations in the proteins involved in the apoptotic regulation have been associated with drug resistance in cancer. Programmed Cell Death 10 (PDCD10) protein is a novel apoptotic regulator that is recently linked to the modulation of cellular proliferation and apoptosis. However, the role of PDCD10 in drug resistance has not been established. In this study, it was aimed to reveal the role of PDCD10 in drug resistance in different cancer cell lines. Gene expression analyses showed that PDCD10 expression was cell- and anti-cancer agent-specific. PDCD10 expression was significantly downregulated in doxorubicin- and docetaxel-resistant MCF7 cells while 2-fold upregulated in doxorubicin-resistant HeLa cells. On the other hand, PDCD10 expression did not show any significant change in doxorubicin-resistant K562 cells, however, more than 2-fold downregulation was observed in imatinib-resistant K562 subline. siRNA-mediated downregulation of PDCD10 expression in parental MCF7 cells resulted in an increase in docetaxel and doxorubicin resistance in these cells. whereas it caused resensitization in doxorubicin-resistant HeLa cells. Similarly, PDCD10 overexpression in parental HeLa cells elevated the resistance to doxorubicin while it promoted chemosensitivity in doxorubicin-resistant MCF7 cells. The downregulation in PDCD10 expression resulted in lower caspase 3/7 activity in MCF7 cells as the cells acquired resistance to etoposide-induced apoptosis. Consequently, the levels of apoptosis-related genes, BCL-2, BAX, SURVIVIN and PUMA, were altered. The results suggest that PDCD10 has a possible dual role in cancer drug resistance, both promoting and preventing the induction of apoptosis under different cellular conditions. PDCD10 could be a novel target for reversal of drug resistance in cancer.

Subject Keywords

Cell death., Apoptosis., Drug resistance., Multidrug resistance.

URI

http://etd.lib.metu.edu.tr/upload/12621966/index.pdf
https://hdl.handle.net/11511/27187

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Graduate School of Natural and Applied Sciences, Thesis

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Citation Formats

Ç. Urfalı Mamatoğlu, “Investigation of the role of programmed cell death 10 (PDCD10) protein in multidrug resistance,” Ph.D. - Doctoral Program, Middle East Technical University, 2018.