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SIRT2 mediates multidrug resistance in acute myelogenous leukemia cells via ERK1/2 signaling pathway

Hua Xu1, Yuanye Li1, Long Chen1

  • 1State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P.R. China.

International Journal of Oncology
|December 10, 2015
PubMed

Insights

Sirtuin 2 (SIRT2) overexpression increases drug resistance in acute myeloid leukemia (AML) by upregulating MRP1 and activating the ERK1/2 pathway. Inhibiting SIRT2 or ERK1/2 enhances chemotherapy sensitivity in AML cells.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Sirtuin 2 (SIRT2) is a NAD+-dependent histone deacetylase implicated in acute myeloid leukemia (AML) cell proliferation and survival.
  • The role of SIRT2 in chemoresistance of AML cells remains largely undefined.
  • Understanding SIRT2's function in drug resistance is crucial for developing effective AML therapies.

Purpose of the Study:

  • To investigate the effect of SIRT2 on drug resistance in chemoresistant AML cells.
  • To elucidate the underlying molecular mechanisms, including the involvement of the ERK1/2 signaling pathway.
  • To assess the therapeutic potential of targeting SIRT2 or ERK1/2 in AML.

Main Methods:

  • Quantitative analysis of SIRT2 expression in AML patient samples and cell lines (HL60 vs. HL60/A).
  • Manipulation of SIRT2 levels using shRNA-mediated depletion and overexpression in AML cells.
  • Assessment of multidrug resistance protein 1 (MRP1) expression, drug accumulation, and apoptosis.
  • Evaluation of ERK1/2 phosphorylation status and the impact of ERK1/2 inhibition using PD98059.

Main Results:

  • SIRT2 expression is elevated in relapsed AML patients and chemoresistant HL60/A cells compared to newly diagnosed patients and sensitive HL60 cells, respectively.
  • SIRT2 depletion reduces MRP1 levels, increases drug accumulation, and enhances apoptosis in HL60/A cells.
  • SIRT2 overexpression increases MRP1 levels, promotes drug efflux, and decreases drug sensitivity in HL60 cells.
  • SIRT2 modulation affects ERK1/2 phosphorylation; inhibiting ERK1/2 potentiates apoptosis in SIRT2-depleted cells and reverses drug resistance in SIRT2-overexpressing cells.

Conclusions:

  • SIRT2 expression positively correlates with resistance to daunorubicin/cytarabine (DNR/Ara-C) and ERK1/2 pathway activity in AML.
  • SIRT2 contributes to DNR/Ara-C resistance in AML cells, at least partially, via the ERK1/2 signaling pathway.
  • Targeting SIRT2 and the ERK1/2 pathway represents a potential strategy to overcome chemotherapy resistance in AML.

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