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SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells.

Wang Z, Yuan H, Roth M, Stark JM, Bhatia R, Chen WY - Oncogene (2012)

Bottom Line: The tyrosine kinase inhibitor imatinib effectively treats CML, but acquired resistance can develop because of BCR-ABL mutations.SIRT1 knockdown also suppresses de novo genetic mutations of hypoxanthine phosphoribosyl transferase gene in CML and non-CML cells upon treatment with DNA damaging agent camptothecin.These results reveal a previously unrecognized role of SIRT1 for promoting mutation acquisition in cancer, and have implication for targeting SIRT1 to overcome CML drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.

ABSTRACT
BCR-ABL transforms bone marrow progenitor cells and promotes genome instability, leading to development of chronic myelogenous leukemia (CML). The tyrosine kinase inhibitor imatinib effectively treats CML, but acquired resistance can develop because of BCR-ABL mutations. Mechanisms for acquisition of BCR-ABL mutations are not fully understood. Using a novel culture model of CML acquired resistance, we show that inhibition of SIRT1 deacetylase by small molecule inhibitors or gene knockdown blocks acquisition of BCR-ABL mutations and relapse of CML cells on tyrosine kinase inhibitors. SIRT1 knockdown also suppresses de novo genetic mutations of hypoxanthine phosphoribosyl transferase gene in CML and non-CML cells upon treatment with DNA damaging agent camptothecin. Although SIRT1 can enhance cellular DNA damage response, it alters functions of DNA repair machineries in CML cells and stimulates activity of error-prone DNA damage repair, in association with acquisition of genetic mutations. These results reveal a previously unrecognized role of SIRT1 for promoting mutation acquisition in cancer, and have implication for targeting SIRT1 to overcome CML drug resistance.

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Pharmacological inhibition of SIRT1 blocked acquired resistance of CML cells on tyrosine kinase inhibitors(a) KCL-22 cells were treated with 50 μM sirtinol or imatinib (STI) alone at the concentrations indicated or in combination of the two drugs. Cells for STI treatment alone all relapsed, and for simplicity, only the 2.5 μM curve was shown. (b) KCL-22 cells were treated with 15 mM nicotinamide (NAM) and 5 μM imatinib alone or in combination. (c) KCL-22 cells were treated with 1μM tenovin-6 and 2.5 μM imatinib alone or in combination. (d) KCL-22 cells were treated with 1μM trichostatin A (TSA) without or with STI at the concentrations indicated. (e) KCL-22 cell relapsed on 2.5 μM Nilotinib (Nil) with T315I mutation, but combination with tenovin-6 or sirtinol blocked relapse. (f) KCL-22 cell relapsed on 1 μM Dasatinib (Das) with T315I mutation. Combination with sirtinol or 5 μM tenovin-6 blocked relapse, and combination with 1 μM tenovin-6 delayed the relapse. (g) Left, sirtinol blocked clonal cells relapse on STI treatment. Right, relapse of clonal KCL-22 cells (L1, L7, Ag3 and Ag11) on STI plus TSA treatment.
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Figure 1: Pharmacological inhibition of SIRT1 blocked acquired resistance of CML cells on tyrosine kinase inhibitors(a) KCL-22 cells were treated with 50 μM sirtinol or imatinib (STI) alone at the concentrations indicated or in combination of the two drugs. Cells for STI treatment alone all relapsed, and for simplicity, only the 2.5 μM curve was shown. (b) KCL-22 cells were treated with 15 mM nicotinamide (NAM) and 5 μM imatinib alone or in combination. (c) KCL-22 cells were treated with 1μM tenovin-6 and 2.5 μM imatinib alone or in combination. (d) KCL-22 cells were treated with 1μM trichostatin A (TSA) without or with STI at the concentrations indicated. (e) KCL-22 cell relapsed on 2.5 μM Nilotinib (Nil) with T315I mutation, but combination with tenovin-6 or sirtinol blocked relapse. (f) KCL-22 cell relapsed on 1 μM Dasatinib (Das) with T315I mutation. Combination with sirtinol or 5 μM tenovin-6 blocked relapse, and combination with 1 μM tenovin-6 delayed the relapse. (g) Left, sirtinol blocked clonal cells relapse on STI treatment. Right, relapse of clonal KCL-22 cells (L1, L7, Ag3 and Ag11) on STI plus TSA treatment.

Mentions: We first treated KCL-22 cells with SIRT1 inhibitors in the presence or absence of imatinib. We found that SIRT1 inhibitors, sirtinol, nicotinamide and tenovin-6, all blocked CML cell relapse when combined with imatinib (Figure 1a–c). Whereas combination of sirtinol with imatinib increased cell death, tenovin-6 blocked the relapse at as low as 1 μM that was below the concentrations to increase imatinib-mediated cell killing (Figure 1c and Supplementary Figure 1). Similarly, nicotinamide blocked cell relapse without enhancing cell death (Figure 1b).


SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells.

Wang Z, Yuan H, Roth M, Stark JM, Bhatia R, Chen WY - Oncogene (2012)

Pharmacological inhibition of SIRT1 blocked acquired resistance of CML cells on tyrosine kinase inhibitors(a) KCL-22 cells were treated with 50 μM sirtinol or imatinib (STI) alone at the concentrations indicated or in combination of the two drugs. Cells for STI treatment alone all relapsed, and for simplicity, only the 2.5 μM curve was shown. (b) KCL-22 cells were treated with 15 mM nicotinamide (NAM) and 5 μM imatinib alone or in combination. (c) KCL-22 cells were treated with 1μM tenovin-6 and 2.5 μM imatinib alone or in combination. (d) KCL-22 cells were treated with 1μM trichostatin A (TSA) without or with STI at the concentrations indicated. (e) KCL-22 cell relapsed on 2.5 μM Nilotinib (Nil) with T315I mutation, but combination with tenovin-6 or sirtinol blocked relapse. (f) KCL-22 cell relapsed on 1 μM Dasatinib (Das) with T315I mutation. Combination with sirtinol or 5 μM tenovin-6 blocked relapse, and combination with 1 μM tenovin-6 delayed the relapse. (g) Left, sirtinol blocked clonal cells relapse on STI treatment. Right, relapse of clonal KCL-22 cells (L1, L7, Ag3 and Ag11) on STI plus TSA treatment.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376246&req=5

Figure 1: Pharmacological inhibition of SIRT1 blocked acquired resistance of CML cells on tyrosine kinase inhibitors(a) KCL-22 cells were treated with 50 μM sirtinol or imatinib (STI) alone at the concentrations indicated or in combination of the two drugs. Cells for STI treatment alone all relapsed, and for simplicity, only the 2.5 μM curve was shown. (b) KCL-22 cells were treated with 15 mM nicotinamide (NAM) and 5 μM imatinib alone or in combination. (c) KCL-22 cells were treated with 1μM tenovin-6 and 2.5 μM imatinib alone or in combination. (d) KCL-22 cells were treated with 1μM trichostatin A (TSA) without or with STI at the concentrations indicated. (e) KCL-22 cell relapsed on 2.5 μM Nilotinib (Nil) with T315I mutation, but combination with tenovin-6 or sirtinol blocked relapse. (f) KCL-22 cell relapsed on 1 μM Dasatinib (Das) with T315I mutation. Combination with sirtinol or 5 μM tenovin-6 blocked relapse, and combination with 1 μM tenovin-6 delayed the relapse. (g) Left, sirtinol blocked clonal cells relapse on STI treatment. Right, relapse of clonal KCL-22 cells (L1, L7, Ag3 and Ag11) on STI plus TSA treatment.
Mentions: We first treated KCL-22 cells with SIRT1 inhibitors in the presence or absence of imatinib. We found that SIRT1 inhibitors, sirtinol, nicotinamide and tenovin-6, all blocked CML cell relapse when combined with imatinib (Figure 1a–c). Whereas combination of sirtinol with imatinib increased cell death, tenovin-6 blocked the relapse at as low as 1 μM that was below the concentrations to increase imatinib-mediated cell killing (Figure 1c and Supplementary Figure 1). Similarly, nicotinamide blocked cell relapse without enhancing cell death (Figure 1b).

Bottom Line: The tyrosine kinase inhibitor imatinib effectively treats CML, but acquired resistance can develop because of BCR-ABL mutations.SIRT1 knockdown also suppresses de novo genetic mutations of hypoxanthine phosphoribosyl transferase gene in CML and non-CML cells upon treatment with DNA damaging agent camptothecin.These results reveal a previously unrecognized role of SIRT1 for promoting mutation acquisition in cancer, and have implication for targeting SIRT1 to overcome CML drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.

ABSTRACT
BCR-ABL transforms bone marrow progenitor cells and promotes genome instability, leading to development of chronic myelogenous leukemia (CML). The tyrosine kinase inhibitor imatinib effectively treats CML, but acquired resistance can develop because of BCR-ABL mutations. Mechanisms for acquisition of BCR-ABL mutations are not fully understood. Using a novel culture model of CML acquired resistance, we show that inhibition of SIRT1 deacetylase by small molecule inhibitors or gene knockdown blocks acquisition of BCR-ABL mutations and relapse of CML cells on tyrosine kinase inhibitors. SIRT1 knockdown also suppresses de novo genetic mutations of hypoxanthine phosphoribosyl transferase gene in CML and non-CML cells upon treatment with DNA damaging agent camptothecin. Although SIRT1 can enhance cellular DNA damage response, it alters functions of DNA repair machineries in CML cells and stimulates activity of error-prone DNA damage repair, in association with acquisition of genetic mutations. These results reveal a previously unrecognized role of SIRT1 for promoting mutation acquisition in cancer, and have implication for targeting SIRT1 to overcome CML drug resistance.

Show MeSH
Related in: MedlinePlus