Subcellular localization determines the delicate balance between the anti- and pro-apoptotic activity of Livin

Nachmias, Boaz; Lazar, Itay; Elmalech, Meital; Abed-El-Rahaman, Ihab; Asshab, Yaqoub; Mandelboim, Ofer; Perlman, Riki; Ben‐Yehuda, Dina

doi:10.1007/s10495-006-0049-1

Cited by 27 publications

(32 citation statements)

References 38 publications

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“…Cisplatin treatment did not change the subcellular localization of Livin A previous report indicated that Livin had both anti-and pro-apoptotic function, which was determined by its different subcellular localization [24]. So we wanted to test the subcellular localization of Livin following cisplatin treatment.…”

Section: Cisplatin Induced Cell Death Was Related To Cell Apoptosismentioning

confidence: 96%

Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells

Ding

Liu

Olsson³

et al. 2012

Tumor Biol.

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The anti-apoptotic factor Livin has been considered critical for tumor progression and poor prognosis for variant types of tumors. But there are only limited reports regarding its expression and biological functions in colon cancer. Here we examined Livin expression in four colon cancer cell lines (HCT116, RKO, KM12C and SW620) in the presence or absence of cisplatin which was used as a model reagent. We found the different response to cisplatin was related to endogenous Livin expression level. From among a panel of apoptosis-related factors (p53, Bcl-2, Bcl-XL, BAX, and survivin), the expression of Livin was up-regulated after cisplatin treatment in a dose-dependent manner. Both the immunocytochemistry and nuclear cytoplasmic fractionation indicated Livin remained in the cytoplasm after treatment with cisplatin. In an attempt to explore the mechanism, we found the elevated expression of Livin was not due to the decreased degradation by proteosome but was enhanced at the mRNA level. Besides, cisplatin treatment activated the mammalian target of rapamycin (mTOR) pathway as shown by increased phosphorylation of Akt1, mTOR, S6K, and 4E-BP1, together with the elevated Livin. The PI3K inhibitor LY294002 inhibited both the phosphorylation of mTOR and up-regulation of Livin. The stable over-expression of Livin inhibited the activation of caspase-3 and led to resistance to cisplatin, while the knock-down of Livin by siRNA rendered colon cancer cells more sensitive to cisplatin. Our study along with others highlighted the potential of Livin for cancer therapy in colon cancer.

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Section: Cisplatin Induced Cell Death Was Related To Cell Apoptosismentioning

confidence: 96%

Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells

Ding

Liu

Olsson³

et al. 2012

Tumor Biol.

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“…34 Also, the anti-or pro-apoptotic function of ML-IAP may be regulated by its subcellular localization, as the pro-apoptotic function of truncated ML-IAP has been linked to its perinuclear localization. 35 Survivin represents the smallest member of the IAP protein family and harbors one BIR domain. 8,9 The ability of survivin to inhibit apoptosis has been attributed to its interaction with Smac, to its binding to XIAP, thereby stabilizing the XIAP protein, and to its inhibitory action on mitochondrial apoptosis.…”

Section: Iaps: Structure and Functionmentioning

confidence: 99%

“…34 The limited proteolysis of ML-IAP by caspase-mediated cleavage exposes an N-terminal domain that is critical for localization of truncated ML-IAP to the perinuclear region and its co-localization with the Golgi apparatus. 35 Although this perinuclear localization of truncated ML-IAP has been described to be essential for its pro-apoptotic function, it was found to be per se not sufficient. 35 Moreover, the RING domain of ML-IAP has been implicated to mediate its proapoptotic function.…”

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confidence: 96%

Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

Fulda

2012

Leukemia

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Resistance to apoptosis is one of the hallmarks of human cancers and contributes to the insensitivity of many cancers to commonly used treatment approaches. Inhibitor of apoptosis (IAP) proteins, a family of anti-apoptotic proteins, have an important role in evasion of apoptosis, as they can both block apoptosis-signaling pathways and promote survival. High expression of IAP proteins is observed in multiple cancers, including hematological malignancies, and has been associated with unfavorable prognosis and poor patients' outcome. Therefore, IAP proteins are currently considered as promising molecular targets for therapy. Indeed, drug-discovery approaches over the last decade aiming at neutralizing IAP proteins have resulted in the generation of small-molecule inhibitors or antisense oligonucleotides that demonstrated in vitro and in vivo antitumor activities in preclinical studies. As some of these strategies have already entered the stage of clinical evaluation, for example, in leukemia, an update on this promising molecular-targeted strategy to interfere with apoptotic pathways is of broad interest.

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“…However, p30-Livin a could be stably expressed and showed significant proapoptotic activity in 721.221 EBV-transformed B-cell line but not p28-Livin h (41). Conversely, it was reported that the greater proapoptotic potency of p28-Livin h was more evident than that of p30-Livin a after transfection in the melanoma cell LB33-MEL.A-1 (42). Therefore, the data derived from the experimental model may define Livin isoforms as proapoptotic agents and lead to novel approaches for cancer treatment; however, the diverse activities between the two isoforms displayed in a wide range of cell apoptosis are still uncertain.…”

Section: Versatile Roles Of Livin In the Apoptotic Cascadementioning

confidence: 99%

“…In their article, full-length Livin is detected exclusively in the cytoplasm, whereas the truncated form (tLivin) is located in a perinucleus with marked localization to the Golgi apparatus; the accumulation of tLivin in the nucleus showed positive correlation with the increase in apoptosis. An extensive mutation study theorized that an intact RING domain was identified as the critical residue for the proapoptotic function of tLivin (42). This may provide a possible mechanism by which the RING motif can increase the activity of caspases indirectly in the cell so that the apoptotic barrier can be lowered to allow the cell to undergo apoptosis.…”

Section: Versatile Roles Of Livin In the Apoptotic Cascadementioning

confidence: 99%

Challenge and promise: roles for Livin in progression and therapy of cancer

Wang

Zhang²,

Liu

et al. 2008

Molecular Cancer Therapeutics

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Livin is a member of the inhibitors of apoptosis protein gene family, which is highly expressed in a variety of human neoplasms. Several studies have shown that down-regulation of Livin expression increases the apoptotic rate, reduces tumor growth potential, and sensitizes tumor cells to chemotherapeutic drugs. Furthermore, emerging data reveal that Livin fragments cleavaged by caspases restored paradoxical proapoptotic activity during the apoptotic process, suggesting that Livin cleavage will become a highly potent proapoptotic agent in the future. In this article, we review the current understanding of the versatile roles of Livin in the apoptotic cascade and exploit the promising approach to interfere with Livin as a novel strategy for cancer therapy. [Mol Cancer Ther 2008;7(12):3661 -9]

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Subcellular localization determines the delicate balance between the anti- and pro-apoptotic activity of Livin

Cited by 27 publications

References 38 publications

Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells

Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells

Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

Challenge and promise: roles for Livin in progression and therapy of cancer

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