Cytotoxic effect of arsenic trioxide on acute promyelocytic leukemia cells through suppression of NFkβ-dependent induction of hTERT due to down-regulation of Pin1 transcription

Abstract

Acute promyelocytic leukemia (APL) is characterized by specific t(15;17), distinct morphologic picture, and clinical coagulopathy that contributes to the morbidity and mortality of the disease. This study was purposed to dissect the molecular mechanisms underlying telomerase-dependent arsenic trioxide (ATO)-induced cytotoxic and anti-proliferative effects in NB4 cells. ATO exposure was associated with transcriptional repression of Pin1, survivin, c-Myc, hTERT, and PinX1 along with an expressive enhancement in p73 mRNA level. Moreover, ATO treatment suppressed cell growth, viability and metabolic activity, exerted apoptosis, hindered telomerase activity, shortened telomere length, and dampened NF-κB activation. On aggregate, these issues indicate that ATO might preempt cell growth and proliferation in NB4 cells through suppression of Pin1-mediated NF-κB-dependent stimulation of telomerase and survivin.

Arsenic trioxide suppresses transcription of hTERT through down-regulation of multiple transcription factors in HL-60 leukemia cells

“…3). Third, it has been reported that Sp1, c-Myc and NFkB can positively regulate the transcription of hTERT (Chou et al, , 2001Ghaffari et al, 2012;Li et al, 2009;Li and Liu, 2003;Tong et al, 2005). Since four putative USF2 binding sites are located in three of the four regions (except À476 to À281), it remains to be determined whether USF2 is a main regulator of the hTERT transcription.…”

“…We previously observed that treatment of HL-60 cells with ATO inhibited the telomerase activity (Zhang et al, 2003(Zhang et al, , 2008. Interestingly, several studies have suggested that arsenic cytotoxicity in APL cells may also be mediated by down-regulation of the human telomerase reverse transcriptase (hTERT) expression (Chou et al, , 2001Ghaffari et al, 2012;Li et al, 2009;Li and Liu, 2003;Tong et al, 2005), though the underlying mechanism remains to be investigated.…”

Demethylation and alterations in the expression level of the cell cycle–related genes as possible mechanisms in arsenic trioxide–induced cell cycle arrest in human breast cancer cells

“…MTT assay was used to determine the suppressive effect of various concentrations of As 2 O 3 at different time intervals (24,48, and 72 h) on proliferation and viability of MCF-7, MDA-MB-231, and MDA-MB-468 cell lines. As shown in Figure 1 In MDA-MB-468 cells, As 2 O 3 induced both S and G2/M arrest and markedly reduced the proportion of cells in G1 phase.…”

“…[20][21][22] Its mechanisms have been intensively studied and are mostly considered to be the induction of cell apoptosis and cell cycle arrest. 23,24 Furthermore, As 2 O 3 exposure has been shown to cause hypomethylation around the promoter region of several tumor suppressor genes leading to their re-expression in various cancer cells. 14,25 The mechanism of DNA hypomethylation after exposure to As 2 O 3 is not clear.…”

The Molecular Mechanisms of Tobacco in Cancer Pathogenesis

“…Among all, PAH and nitrosamine are two most important components with carcinogenic properties (9,10). Moreover, there is a compelling body of evidence which introduces arsenic as another important carcinogen in ciggerettes (11). Some researchers believe that smoking during pregnancy increases the risk of cancer in children (12).…”