Dual Mechanisms of sHA 14-1 in Inducing Cell Death through Endoplasmic Reticulum and Mitochondria

Hermanson, David; Addo, Sadiya N.; Bajer, Anna; Marchant, Jonathan S.; Das, Sonia G.; Balasubramanian, S.; Al-Mousa, Fawaz; Michelangeli, Francesco; Thomas, David D.; LeBien, Tucker W.; Xing, Chengguo

doi:10.1124/mol.109.055830

Cited by 48 publications

(49 citation statements)

References 65 publications

(101 reference statements)

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“…5B). Note that Z-VAD-FMK also induced cell death, including apoptosis, which is consistent with previous studies (28,29). Accordingly, Z-VAD-FMK may cause endoplasmic reticulum (ER) stress and thus induce apoptosis (30)(31)(32).…”

Section: Discussionsupporting

confidence: 78%

Activation of caspases and apoptosis in response to low-voltage electric pulses

Matsuki

Takeda²,

Ishikawa³

et al. 2010

Oncol Rep

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Abstract. Few studies have examined apoptosis induced by low-voltage electric pulses (LVEPs). LVEP-induce changes in membrane potential that are below the membrane breakdown threshold and increase membrane permeability without electroporation (pore formation) through the transport of extracellular substances via phagocytosis. We demonstrated that propidium iodide uptake and apoptosis increased in accordance with the duration and number of LVEPs in B16 cells, which showed relatively good viability under mild electric field conditions. We showed that LVEP-induced apoptosis was achieved through caspase-8 and -9 activation and subsequent caspase-3 activation. Long-duration LVEPs caused only mild cell damage, such that the apoptosis ratio (apoptosis/total cell death) in electric pulse-treated cells was similar to that in non-treated control cells. To assess the relative degree of caspase dependency in LVEP-induced apoptosis, the apoptosis rate and caspase-3 activity were analyzed using a pan-caspase inhibitor (Z-VAD-FMK). Z-VAD-FMK treatment inhibited, but did not abolish, LVEP-induced apoptosis, indicating that caspases other than caspase-3 participate in this pathway. Moreover, LVEP treatment inhibited cell growth, suggesting that LVEP treatment may be a valuable anticancer therapy. Although the mechanism of LVEP-induced apoptosis remains unclear, it may be related to dysfunctional membrane transport of Ca 2+ and other extracellular substances involved in caspase activation.

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Section: Discussionsupporting

confidence: 78%

Activation of caspases and apoptosis in response to low-voltage electric pulses

Matsuki

Takeda²,

Ishikawa³

et al. 2010

Oncol Rep

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Section: Discussionmentioning

confidence: 99%

“…Notably, inhibition of BCL2 proteins has been previously shown to result in calcium depletion in pancreatic and leukemia cells. 36,37 Because ABT-737-induced apoptosis in platelets was not affected by chelation of extracellular calcium, 24 it is possible that the effect of BCL2/BCL-X L inhibition on calcium is unrelated and independent of its apoptosis-inducing effects.The ultrastructural characteristics of apoptotic platelets are not, as yet, well defined. Cytoplasmic condensation and budding, to yield microparticles, have been associated with apoptosis in aging platelets in stored concentrates, 18 but these platelets have also undergone a degree of activation during their preparation, which increased during storage in parallel with their decline into an apoptotic-like state.…”

mentioning

confidence: 99%

BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation

Vogler

Hamali

Sun

et al. 2011

Blood

166

147

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Apoptosis in megakaryocytes results in the formation of platelets. The role of apoptotic pathways in platelet turnover and in the apoptotic-like changes seen after platelet activation is poorly understood. ABT-263 (Navitoclax), a specific inhibitor of antiapoptotic BCL2 proteins, which is currently being evaluated in clinical trials for the treatment of leukemia and other malignancies, induces a doselimiting thrombocytopenia. In this study, the relationship between BCL2/BCL-X L inhibition, apoptosis, and platelet activa- IntroductionAll nucleated cells in multicellular organisms are genetically programmed to undergo apoptosis to remove unnecessary or damaged cells from the whole organism. This program has been recognized as the central mechanism of platelet production from megakaryocytes. 1 However, the role of apoptosis in anuclear, mature platelets is less well characterized, with apoptotic-like changes seen in both aging platelets and in the formation of procoagulant microparticles after agonist stimulation.Two main pathways lead to the execution of apoptosis: the extrinsic and the intrinsic (or mitochondrial) pathways. Both converge into the activation of caspases, which are proteases that cleave Ͼ 500 cellular targets and induce typical morphologic changes associated with apoptosis in nucleated cells. A critical step in the intrinsic pathway is the loss of mitochondrial membrane potential (MMP) and the release of cytochrome c into cytosol, where it triggers the activation of caspase-9. Therefore, the release of cytochrome c from mitochondria needs to be tightly regulated: a function that is fulfilled by the BCL2 protein family, which consists of proapoptotic and antiapoptotic members that promote or block the release of cytochrome c, respectively. 2,3 The proapoptotic family members BAX and BAK play an essential role in directly mediating the release of cytochrome c by forming a pore in the outer mitochondrial membrane. Antiapoptotic BCL2 proteins, including BCL2, BCL-X L , BCL-w, MCL1, and BCL2A1, prevent the activation of BAX and BAK. Besides their function in regulating mitochondrial cytochrome c release, BCL2 proteins have also been implicated in the regulation of intracellular calcium homeostasis at the endoplasmic reticulum (ER), possibly by interacting with inositol triphosphate receptors. 4,5 Because of their key role, the antiapoptotic BCL2 proteins are attractive targets for anticancer therapy, with several small molecule inhibitors currently in preclinical testing or early clinical trials. 6,7 Among these, the most promising and specific inhibitors are ABT-263 (Navitoclax) and 9 ABT-737 shows promising antitumor activity in animal models of leukemia and lymphoma. A related compound, ABT-263, is metabolically more stable and currently in phase 1 and 2 clinical trials for leukemia and other malignancies. 10 Both compounds have often been regarded as interchangeable because they bind with high affinity to BCL2, BCL-X L , and BCL-w but do not inhibit MCL1 or BCL2A1. 11 Early results from the clinica...

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“…This inhibitory effect of HA14-1 on SERCA might account for its ability to kill cells in a caspase-independent manner (Vogler et al, 2009). Also, a stabilized version of this compound (sHA14-1) has been reported to display a dual action, including inhibition of Bcl-2 at the mitochondrial level and inhibition of SERCA by impacting its Ca 2+ -ATPase activity (Hermanson et al, 2009). In this study, it was proposed that the dual action of sHA14-1 was needed to cause cell death, since thapsigargin, an irreversible SERCA inhibitor without reported impact on anti-apoptotic Bcl-2 proteins, failed to induce mitochondrial depolarization and induction of the apoptosis cascade.…”

Section: While This Peptide By Itself Is Not Cytotoxic In Non-maligmentioning

confidence: 99%

HA14-1 potentiates apoptosis in B-cell cancer cells sensitive to a peptide disrupting IP3 receptor / Bcl-2 complexes

Akl

Rovere²,

Janssens³

et al. 2015

Int. J. Dev. Biol.

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Dual Mechanisms of sHA 14-1 in Inducing Cell Death through Endoplasmic Reticulum and Mitochondria

Cited by 48 publications

References 65 publications

Activation of caspases and apoptosis in response to low-voltage electric pulses

Activation of caspases and apoptosis in response to low-voltage electric pulses

BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation

HA14-1 potentiates apoptosis in B-cell cancer cells sensitive to a peptide disrupting IP3 receptor / Bcl-2 complexes

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