Arsenic trioxide–induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL

Li, Qun; Hilsenbeck, Susan G.; Gazitt, Yair

doi:10.1182/blood-2002-10-3231

Cited by 194 publications

(193 citation statements)

References 44 publications

Supporting

Mentioning

170

Contrasting

Order By: Relevance

“…However, arsenite induced profound changes of susceptibility of melanoma to exogenous recombinant TRAIL by up-regulation of TRAIL-R1 and R2 surface expression and JNK-cJun-mediated down-regulation of cFLIP levels. Published reports indicate that myeloma cells display synergistic activation of TRAIL-mediated apoptosis by arsenic [44,45]. However, we observed largely additive effects of such combined treatment.…”

Section: Discussioncontrasting

confidence: 52%

See 1 more Smart Citation

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

Ivanov

Hei

2006

Experimental Cell Research

View full text Add to dashboard Cite

AP-1/cJun, NF-κB and STAT3 transcription factors control expression of numerous genes, which regulate critical cell functions including proliferation, survival and apoptosis. Sodium arsenite is known to suppress both the IKK-NF-κB and JAK2-STAT3 signaling pathways and to activate the MAPK/JNK-cJun pathways, thereby committing some cancers to undergo apoptosis. Indeed, sodium arsenite is an effective drug for the treatment of acute promyelocytic leukemia with little nonspecific toxicity. Malignant melanoma is highly refractory to conventional radio-and chemotherapy. In the present study we observed strong effects of sodium arsenite treatment on upregulation of TRAILmediated apoptosis in human and mouse melanomas. Arsenite treatment upregulated surface levels of death receptors, TRAIL-R1 and TRAIL-R2, through increased translocation of these proteins from cytoplasm to the cell surface. Furthermore, activation of cJun and suppression of NF-κB by sodium arsenite resulted in upregulation of the endogenous TRAIL-and downregulation of the cFLIP gene expression (which encodes one of the main anti-apoptotic proteins in melanomas) followed by cFLIP protein degradation and, finally, by acceleration of TRAIL-induced apoptosis. Direct suppression of cFLIP expression by cFLIP RNAi also accelerated TRAIL-induced apoptosis in these melanomas, while COX-2 suppression substantially increased levels of both TRAIL-induced and arsenite-induced apoptosis. In contrast, overexpression of permanently active AKTmyr inhibited TRAIL-mediated apoptosis via down-regulation of TRAIL-R1 levels. Finally, AKT overactivation increased melanoma survival in cell culture and dramatically accelerated growth of melanoma transplant in vivo, highlighting a role of AKT suppression for effective anti-cancer treatment.

show abstract

Section: Discussioncontrasting

confidence: 52%

“…These results further suggested an effect of sodium arsenite on the regulation of TRAIL-R1 protein trafficking to the cell surface. Upregulation of TRAIL-R surface levels by arsenite treatment was previously observed for multiple myelomas [44] and some leukemic cell lines [45].…”

Section: Role Of Sodium Arsenite Treatment In the Regulation Of The Esupporting

confidence: 56%

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

Ivanov

Hei

2006

Experimental Cell Research

View full text Add to dashboard Cite

show abstract

“…Furthermore, neither inhibition of caspase-9 nor usage of caspase-9 DN mutants substantially blocked As 2 O 3 -mediated cell demise. To our notion, our results do not conflict with recently published data where As 2 O 3 was reported to massively induce apoptosis and to facilitate caspase-8, -9, and -3 processing (Liu et al, 2003). Notably, the authors assessed cell death by staining cells with annexin-V-FITC only without counterstaining with PI.…”

Section: Discussioncontrasting

confidence: 51%

Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway

et al. 2005

View full text Add to dashboard Cite

Arsenic trioxide (As 2 O 3 , arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed especially for the treatment of acute promyelocytic leukemia. There and in lymphoid cells, we demonstrated that As 2 O 3 induces cell death in a caspase-2-and -9-independent fashion. Here, we address a potential role of death receptor signaling through the FADD/caspase-8 death-inducing signaling complex in As 2 O 3 -induced cell death. In detail, we demonstrate that As 2 O 3 induces cell death independently of caspase-8 or FADD and cannot be blocked by disruption of CD95/Fas receptor ligand interaction. Unlike in death receptor ligation-induced apoptosis, As 2 O 3 -induced cell death was not blocked by the broad-spectrum caspase inhibitor z-VAD-fmk or the caspase-8-specific inhibitor z-IETDfmk. Nevertheless, As 2 O 3 -induced cell death occurred in a regulated manner and was abrogated upon Bcl-2 overexpression. In contrast, As 2 O 3 -induced cell demise was neither blocked by the caspase-9 inhibitor z-LEHD-fmk nor substantially inhibited through the expression of a dominant negative caspase-9 mutant. Altogether our data demonstrate that As 2 O 3 -induced cell death occurs independently of the extrinsic death receptor pathway of apoptosis. Cell death proceeds entirely via an intrinsic, Bcl-2-controlled mitochondrial pathway that does, however, not rely on caspase-9.

show abstract

“…Indeed, As 2 O 3 activates the MAPK signaling pathways (Cavigelli et al, 1996;Meriin et al, 1999;Verma et al, 2002) and therefore induces the phosphorylation of a subset of transcription factors (AP-1, Elk, ATF2, CREB and others) (Bebien et al, 2003), PML (Hayakawa and Privalsky, 2004) and histones (Li et al, 2002(Li et al, , 2003aHe et al, 2003). This leads to the increased transcription of critical apoptosisand proliferation-associated genes including among others, the proto-oncogenes c-fos, c-jun and Egr-1 (Lim et al, 1998;Bernstam and Nriagu, 2000;Liu et al, 2003) and caspases (Li et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid and arsenic trioxide cooperate for apoptosis through phosphorylated RXR alpha

et al. 2005

View full text Add to dashboard Cite

Arsenite trioxide (As 2 O 3 ) induces apoptosis in several cell lines by disturbing key signal transduction pathways through its oxidative properties. Here, we report that As 2 O 3 also induces the phosphorylation of the retinoid receptor RXRa, subsequent to oxidative damages and the activation of the stress-activated protein kinases cascade (JNKs). We also report that RA amplifies both As 2 O 3 -induced phosphorylation of RXRa and apoptosis. Taking advantage of 'rescue' F9 cell lines expressing RXRa mutated at its phosphorylation sites, in an RXRa null background, we provide evidence that RXRa is a key element involved in that potentiating effect. Finally, we demonstrate that As 2 O 3 also abrogates the transactivation of RA-target genes.

show abstract

Arsenic trioxide–induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL

Cited by 194 publications

References 44 publications

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway

Retinoic acid and arsenic trioxide cooperate for apoptosis through phosphorylated RXR alpha

Contact Info

Product

Resources

About