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

Abstract

SIRT2, one of nicotinamide adenine dinucleotide (NAD+)-dependent class Ⅲ histone deacetylase family proteins, has been found to be involved in the proliferation and survival of acute myeloid leukemia (AML) cells. However, its effect on drug resistance on chemoresistant AML cells is unclear. In the present study, we first found that SIRT2 was expressed at higher level in the relapsed AML patients than the newly diagnosed patients. Consistent with this observation, the expression level of SIRT2 was higher in HL60/A cells than that in HL60 cells. Depletion of SIRT2 by shRNAs in HL60/A cells resulted in decreased MRP1 level, enhanced drug accumulation and triggered more apoptosis. By contrast, overexpression of SIRT2 in HL60 cells led to increased MRP1 level, drug efflux and attenuated drug sensitivity. Moreover, the decreased expression of phosphorylated ERK1/2 was detected in SIRT2-depleted HL60/A cells and increased expression of phosphorylated ERK1/2 was observed in SIRT2 overexpressed HL60 cells. Furthermore, blockage of ERK1/2 signaling pathway with the chemical inhibitor PD98059, further induced apoptosis of HL60/A cells conferred by SIRT2 depletion. Importantly, ERK1/2 inhibition was able to reverse the drug resistance of HL60 conferred by SIRT2 overexpression. Thus, our findings collectively suggested that the expression level of SIRT2 has a positive relationship with DNR/Ara-C resistance and activity of ERK1/2 signaling pathway. SIRT2 might regulate DNR/Ara-C sensitivity in AML cells at least partially through the ERK1/2 pathway.

The role of SIRT2 in cancer: A novel therapeutic target

“…Li et al found that SIRT2 acts on the NF-κB-miR-21 signal pathway, delycytates p65 K310 points, prevents p65 from binding to the miR-21 promoter region, inhibits its transcription, thereby inhibiting tumor proliferation and cloning formation, and by raising caspase 3 and Bax Protein levels induce apoptosis 49. Chemotherapy is one of the most important means of treatment of malignant tumors, however, it is often due to the emergence of tumor cell resistance leading to treatment failure 50. Experiments have shown that SIRT2 can regulate tumor proliferation by inhibiting the MAP kinase pathway, and SIRT2 deficiency leads to cell resistance to drugs acting on the RTK-RAS/RAF-MEK-ERK pathway 51.…”

SIRT2 is an unfavorable prognostic biomarker in patients with acute myeloid leukemia

“…SIRT2 is the primary cytoplasmic surtuin but shuttles continuously between cytoplasmic and nuclear comparts during interphase, and it is found to be involved in the proliferation and survival of acute myeloid leukemia. Levels of SIRT2 mRNA significantly elevated in AML blasts compared to levels in bone marrow from healthy individuals and in a high-risk group pf AML patients, it is significantly higher than that in a standard-risk group 13 . FAB subtypes M1, M2 and M4 patients have lower levels of SIRT2 while M5 patients have higher levels.…”

“…Besides, SIRT2 participates in the aberrant proliferation and survival of leukemic cell, and inhibition of SIRT2 by compunds leads to induced cell cycle arrest, elevated apoptosis, reduced proliferation and granulocytic differentiation in AML 14 15 16 17 . It is also suggested that high SIRT2 expression leads to DNR/Ara-C resistance in AML cells through the ERK1/2 pathway 13 . What’s more, some studies also demonstrate that inhibiting SIRT2 with compounds acetylate and activate the tumor suppressor TP53, which is critical for controlling cell growth and apoptosis during cellular stress, and mutations of which are an unfavorable prognostic factor in patients with AML 18 19 .…”

Low expression of NCALD is associated with chemotherapy resistance and poor prognosis in epithelial ovarian cancer

“…Erk1/2 is an important component of the cascade of Ras-Raf-MEK-ERK signaling pathway, which has received extensive attention in tumor resistance and tumor therapy [27][28][29]. It is activated in many cisplatin treated cell lines [30][31][32][33]. In the resting state, ERK1/2 binds to MEK in the cytoplasm.…”