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Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma.

McCabe KE, Bacos K, Lu D, Delaney JR, Axelrod J, Potter MD, Vamos M, Wong V, Cosford ND, Xiang R, Stupack DG - Cell Death Dis (2014)

Bottom Line: This challenge has fostered the development of novel approaches to treatment, including antagonists of the 'inhibitor of apoptosis proteins' (IAPs), also called SMAC mimetics, as apoptosis-inducing agents whose action is opposed by caspase inhibitors.The formation of a necrosome-like complex with a second critical effector, receptor-interacting serine-threonine kinase-1 (RIPK1), was observed.RIPK1, RIPK3 and TNFα were required for the induction of death, as agents that inhibit the function of any of these targets prevented cell death.

View Article: PubMed Central - PubMed

Affiliation: Department of Reproductive Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.

ABSTRACT
Ovarian cancer patients are typically treated with carboplatin and paclitaxel, but suffer a high rate of relapse with recalcitrant disease. This challenge has fostered the development of novel approaches to treatment, including antagonists of the 'inhibitor of apoptosis proteins' (IAPs), also called SMAC mimetics, as apoptosis-inducing agents whose action is opposed by caspase inhibitors. Surprisingly, IAP antagonist plus caspase inhibitor (IZ) treatment selectively induced a tumor necrosis factor-α (TNFα)-dependent death among several apoptosis-resistant cell lines and patient xenografts. The induction of necroptosis was common in ovarian cancer, with expression of catalytically active receptor-interacting protein kinase-3 (RIPK3) necessary for death, and in fact sufficient to compromise survival of RIPK3-negative, necroptosis-resistant ovarian cancer cells. The formation of a necrosome-like complex with a second critical effector, receptor-interacting serine-threonine kinase-1 (RIPK1), was observed. RIPK1, RIPK3 and TNFα were required for the induction of death, as agents that inhibit the function of any of these targets prevented cell death. Abundant RIPK3 transcript is common in serous ovarian cancers, suggesting that further evaluation and targeting of this RIPK3-dependent pathway may be of clinical benefit.

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Related in: MedlinePlus

RIPK1 suppression compromises I+Z-mediated death in ovarian cancer cells. (a) The effect of suppression of RIPK1 expression by shRNA (see inset) on OVCAR3 cell death was examined following treatment with I (1 μM), Z (20 μM), necrostatin (Nec), diluent controls (Con) or combinations of these agents as shown for 48 h. (b) The effect of suppression of the adaptor protein FADD (inset) was similarly evaluated. Mean±S.D. of triplicates from representative experiments are shown. *P<0.05 versus control
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fig3: RIPK1 suppression compromises I+Z-mediated death in ovarian cancer cells. (a) The effect of suppression of RIPK1 expression by shRNA (see inset) on OVCAR3 cell death was examined following treatment with I (1 μM), Z (20 μM), necrostatin (Nec), diluent controls (Con) or combinations of these agents as shown for 48 h. (b) The effect of suppression of the adaptor protein FADD (inset) was similarly evaluated. Mean±S.D. of triplicates from representative experiments are shown. *P<0.05 versus control

Mentions: All of the ovarian cancer tumor cell lines examined expressed RIPK1, and its expression was not sufficient for, or predictive of, cell death following I or IZ treatment (Figure 1b). As necrostatin-1 inhibited cell death, we next silenced RIPK1 expression (Figure 3a, inset) and then evaluated cell survival following exposure to IZ. As shown, the loss of RIPK1 was protective, consistent with the necrostatin sensitivity of the death pathway (Figure 3a). By contrast, the knockdown of the adaptor protein FADD had a more modest effect (Figure 3b), suggesting that FADD may provide some facilitating role in necroptosis in the ovarian cancer cells, yet was not critical in facilitating RIPK1 to RIPK3 signaling.


Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma.

McCabe KE, Bacos K, Lu D, Delaney JR, Axelrod J, Potter MD, Vamos M, Wong V, Cosford ND, Xiang R, Stupack DG - Cell Death Dis (2014)

RIPK1 suppression compromises I+Z-mediated death in ovarian cancer cells. (a) The effect of suppression of RIPK1 expression by shRNA (see inset) on OVCAR3 cell death was examined following treatment with I (1 μM), Z (20 μM), necrostatin (Nec), diluent controls (Con) or combinations of these agents as shown for 48 h. (b) The effect of suppression of the adaptor protein FADD (inset) was similarly evaluated. Mean±S.D. of triplicates from representative experiments are shown. *P<0.05 versus control
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4237265&req=5

fig3: RIPK1 suppression compromises I+Z-mediated death in ovarian cancer cells. (a) The effect of suppression of RIPK1 expression by shRNA (see inset) on OVCAR3 cell death was examined following treatment with I (1 μM), Z (20 μM), necrostatin (Nec), diluent controls (Con) or combinations of these agents as shown for 48 h. (b) The effect of suppression of the adaptor protein FADD (inset) was similarly evaluated. Mean±S.D. of triplicates from representative experiments are shown. *P<0.05 versus control
Mentions: All of the ovarian cancer tumor cell lines examined expressed RIPK1, and its expression was not sufficient for, or predictive of, cell death following I or IZ treatment (Figure 1b). As necrostatin-1 inhibited cell death, we next silenced RIPK1 expression (Figure 3a, inset) and then evaluated cell survival following exposure to IZ. As shown, the loss of RIPK1 was protective, consistent with the necrostatin sensitivity of the death pathway (Figure 3a). By contrast, the knockdown of the adaptor protein FADD had a more modest effect (Figure 3b), suggesting that FADD may provide some facilitating role in necroptosis in the ovarian cancer cells, yet was not critical in facilitating RIPK1 to RIPK3 signaling.

Bottom Line: This challenge has fostered the development of novel approaches to treatment, including antagonists of the 'inhibitor of apoptosis proteins' (IAPs), also called SMAC mimetics, as apoptosis-inducing agents whose action is opposed by caspase inhibitors.The formation of a necrosome-like complex with a second critical effector, receptor-interacting serine-threonine kinase-1 (RIPK1), was observed.RIPK1, RIPK3 and TNFα were required for the induction of death, as agents that inhibit the function of any of these targets prevented cell death.

View Article: PubMed Central - PubMed

Affiliation: Department of Reproductive Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.

ABSTRACT
Ovarian cancer patients are typically treated with carboplatin and paclitaxel, but suffer a high rate of relapse with recalcitrant disease. This challenge has fostered the development of novel approaches to treatment, including antagonists of the 'inhibitor of apoptosis proteins' (IAPs), also called SMAC mimetics, as apoptosis-inducing agents whose action is opposed by caspase inhibitors. Surprisingly, IAP antagonist plus caspase inhibitor (IZ) treatment selectively induced a tumor necrosis factor-α (TNFα)-dependent death among several apoptosis-resistant cell lines and patient xenografts. The induction of necroptosis was common in ovarian cancer, with expression of catalytically active receptor-interacting protein kinase-3 (RIPK3) necessary for death, and in fact sufficient to compromise survival of RIPK3-negative, necroptosis-resistant ovarian cancer cells. The formation of a necrosome-like complex with a second critical effector, receptor-interacting serine-threonine kinase-1 (RIPK1), was observed. RIPK1, RIPK3 and TNFα were required for the induction of death, as agents that inhibit the function of any of these targets prevented cell death. Abundant RIPK3 transcript is common in serous ovarian cancers, suggesting that further evaluation and targeting of this RIPK3-dependent pathway may be of clinical benefit.

Show MeSH
Related in: MedlinePlus