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<title>Blebbishield emergency program</title>

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<span id="openzim-page-title" class="mw-page-title-main"><span class="mw-page-title-main">Blebbishield emergency program</span></span>

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<p><b>Blebbishield emergency program</b> is a process which acts as a last line of defense for <a href="Cancer_stem_cells" class="mw-redirect" title="Cancer stem cells">cancer stem cells</a> after induction of <a href="Apoptosis" title="Apoptosis">apoptosis</a> where the apoptotic <a href="Bleb_(cell_biology)" title="Bleb (cell biology)">blebs</a> fuse to shield the cells/nucleus from the destructive force of apoptosis by forming blebbishields. Blebbishields in turn fuse to each other and generate cancer stem cell spheres/cellular transformation, essentially shifting the balance of dying cells back towards survival.

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<div class="mw-heading mw-heading2"><h2 id="Discovery">Discovery</h2></div>

<p>Blebbishields were first identified in human <a href="Bladder_cancer" title="Bladder cancer">bladder cancer</a> cell line RT4 (HTB-2: ATCC), referred to as RT4P (RT4 parent) in the initial report. <sup id="cite_ref-auto_1-0" class="reference"><a href="#cite_note-auto-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading2"><h2 id="Blebbishield_formation">Blebbishield formation</h2></div>

<p>Every cell type, especially cancer cells, are capable of undergoing apoptosis, a process in which the <a href="Plasma_membrane" class="mw-redirect" title="Plasma membrane">plasma membrane</a> undergoes blebbing followed by orderly deconstruction of cells into apoptotic bodies. <a href="Cancer_stem_cells" class="mw-redirect" title="Cancer stem cells">Cancer stem cells</a> have the extraordinary ability to construct blebbishields from these apoptotic bodies by bleb-bleb fusion and form stem cell spheres/cellular transformation by sub-sequent blebbishield-blebbishield fusion.<sup id="cite_ref-auto_1-1" class="reference"><a href="#cite_note-auto-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-2" class="reference"><a href="#cite_note-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup> Endocytosis and endocytosis-driven serpentine filopodia are necessary to tether and tie apoptotic bodies to facilitate fusion.<sup id="cite_ref-Endo_3-0" class="reference"><a href="#cite_note-Endo-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup> The involvement of <a href="Membrane_fusion" class="mw-redirect" title="Membrane fusion">membrane fusion</a> was confirmed by inhibiting <a href="Cholesterol" title="Cholesterol">cholesterol</a> using the cholesterol antagonist Filipin-III.<sup id="cite_ref-auto_1-2" class="reference"><a href="#cite_note-auto-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading2"><h2 id="Blebbishields_and_cancer_stem_cells">Blebbishields and cancer stem cells</h2></div>

<p>Sphere forming cells widely display characteristics of <a href="Tumorigenesis" class="mw-redirect" title="Tumorigenesis">tumorigenesis</a>. Cells from blebbishield derived spheres are tumorigenic in nature, providing an important clue for tumorigenesis. Blebbishield emergency program is postulated to have the strong rationale for bladder cancer recurrence as it is a potential cause for multifocal/satellite bladder tumors.<sup id="cite_ref-4" class="reference"><a href="#cite_note-4"><span class="cite-bracket">[</span>4<span class="cite-bracket">]</span></a></sup> The blebbishield derived cells exhibit strong <a href="Drug_resistance" title="Drug resistance">drug resistance</a> behavior and exhibit high sensitivity to <a href="Bisbenzimide" title="Bisbenzimide">Hoechst-33342</a> similar to <a href="Side_population" title="Side population">side-population</a> cells.<sup id="cite_ref-auto_1-3" class="reference"><a href="#cite_note-auto-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading2"><h2 id="Positive_and_negative_regulators_of_blebbishield_survival">Positive and negative regulators of blebbishield survival</h2></div>

<div class="mw-heading mw-heading3"><h3 id="Caspases">Caspases</h3></div>

<p>Caspases (<a href="Caspase-3" class="mw-redirect" title="Caspase-3">Caspase-3</a>, <a href="Caspase-8" class="mw-redirect" title="Caspase-8">caspase-8</a>, <a href="Caspase-9" title="Caspase-9">caspase-9</a>) are found to have important roles in contributing the formation of blebbishields as well as sub-sequent cancer stem cell spheres.<sup id="cite_ref-auto_1-4" class="reference"><a href="#cite_note-auto-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup> Caspase-3 plays a dual role where it is needed for induction of proper apoptosis:<sup id="cite_ref-auto_1-5" class="reference"><a href="#cite_note-auto-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup> to activate Bax and Bak by cleavage to kill the cells and also needed for transformation from blebbishields.<sup id="cite_ref-auto1_5-0" class="reference"><a href="#cite_note-auto1-5"><span class="cite-bracket">[</span>5<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading3"><h3 id="VEGF_signaling">VEGF signaling</h3></div>

<p><a href="VEGF" class="mw-redirect" title="VEGF">VEGF</a> signaling, especially <a href="Vascular_endothelial_growth_factor" title="Vascular endothelial growth factor">VEGF-A</a> to VEGFR2 signaling plays a commanding role during the transformation from blebbishields.<sup id="cite_ref-Endo_3-1" class="reference"><a href="#cite_note-Endo-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup> VEGF signaling leads to <a href="N-myc_internal_ribosome_entry_site_(IRES)" title="N-myc internal ribosome entry site (IRES)">IRES translation of N-Myc</a>, which in concert with mitochondrial oligomers to boost glycolysis to power blebbishield formation and transformation from blebbishields.<sup id="cite_ref-auto1_5-1" class="reference"><a href="#cite_note-auto1-5"><span class="cite-bracket">[</span>5<span class="cite-bracket">]</span></a></sup> <a href="Lactic_acid" title="Lactic acid">Lactic acid</a>, a tumor derived metabolite, altering <a href="PH" title="PH">pH</a> of <a href="Tumor_microenvironment" title="Tumor microenvironment">tumor microenvironment</a> enhances sphere formation from blebbishields positively regulating VEGF bioavailability.<sup id="cite_ref-auto_1-6" class="reference"><a href="#cite_note-auto-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading3"><h3 id="Reactive_oxygen_species_[ROS]">Reactive oxygen species [ROS]</h3></div>

<p><a href="Reactive_oxygen_species" title="Reactive oxygen species">Reactive oxygen species</a> plays a role in cellular transformation. Various PKC isoforms were implicated in p47phox/Nox1 axis mediated ROS generation during cellular transformation. PKC-ζ isoform interaction with p47phox was found to be critical for ROS production and transformation from blebbishields.<sup id="cite_ref-6" class="reference"><a href="#cite_note-6"><span class="cite-bracket">[</span>6<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading3"><h3 id="Role_of_mitochondria_and_Glycolysis_in_blebbishield_emergency_program">Role of mitochondria and Glycolysis in blebbishield emergency program</h3></div>

<p>Protection of <a href="Mitochondria" class="mw-redirect" title="Mitochondria">mitochondria</a> from outer membrane permeabilization is important to retain the transforming potential of blebbishields.<sup id="cite_ref-7" class="reference"><a href="#cite_note-7"><span class="cite-bracket">[</span>7<span class="cite-bracket">]</span></a></sup> Functional mitochondria lead to uninterrupted glycolysis which in turn protects the blebbishields from secondary necrosis. <a href="K-Ras" class="mw-redirect" title="K-Ras">K-Ras</a>, <a href="Bcl-2-associated_death_promoter" title="Bcl-2-associated death promoter">BAD</a> (phosphorylated at Ser-112), <a href="P27_(gene)" class="mw-redirect" title="P27 (gene)">p27</a>, <a href="Bcl-2-associated_X_protein" class="mw-redirect" title="Bcl-2-associated X protein">Bax</a> and <a href="Bcl-2_homologous_antagonist_killer" title="Bcl-2 homologous antagonist killer">Bak</a> forms oligomers to boost <a href="Glycolysis" title="Glycolysis">glycolysis</a>, which in turn overrides secondary necrosis and offer energy required to proceed with the reconstruction process during cellular transformation from blebbishields.<sup id="cite_ref-auto1_5-2" class="reference"><a href="#cite_note-auto1-5"><span class="cite-bracket">[</span>5<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading3"><h3 id="Other_factors">Other factors</h3></div>

<p><a href="N-linked_glycosylation" title="N-linked glycosylation">N-linked glycosylation</a> and <a href="V-ATPase" title="V-ATPase">v-ATPase</a> were implicated to have survival roles in blebbishield emergency program.<sup id="cite_ref-auto_1-7" class="reference"><a href="#cite_note-auto-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading2"><h2 id="References">References</h2></div>

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<li id="cite_note-auto-1"><span class="mw-cite-backlink">^ <a href="#cite_ref-auto_1-0"><sup><i><b>a</b></i></sup></a> <a href="#cite_ref-auto_1-1"><sup><i><b>b</b></i></sup></a> <a href="#cite_ref-auto_1-2"><sup><i><b>c</b></i></sup></a> <a href="#cite_ref-auto_1-3"><sup><i><b>d</b></i></sup></a> <a href="#cite_ref-auto_1-4"><sup><i><b>e</b></i></sup></a> <a href="#cite_ref-auto_1-5"><sup><i><b>f</b></i></sup></a> <a href="#cite_ref-auto_1-6"><sup><i><b>g</b></i></sup></a> <a href="#cite_ref-auto_1-7"><sup><i><b>h</b></i></sup></a></span> <span class="reference-text">Jinesh GG, Choi W, Shah JB, Lee EK, Willis DL, Kamat AM. <a rel="nofollow" class="external text" href="http://www.nature.com/cdd/journal/v20/n3/full/cdd2012140a.html">Blebbishields, the emergency program for cancer stem cells: sphere formation and tumorigenesis after apoptosis</a>. Cell Death Differ. 2013 Mar;20(3):382-95.</span>

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<li id="cite_note-2"><span class="mw-cite-backlink"><b><a href="#cite_ref-2">^</a></b></span> <span class="reference-text">Jinesh GG, Kamat AM. <a rel="nofollow" class="external text" href="http://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd201626a.html">Blebbishield emergency program: an apoptotic route to cellular transformation</a>. Cell Death Differ. 2016 In Press.</span>

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<li id="cite_note-Endo-3"><span class="mw-cite-backlink">^ <a href="#cite_ref-Endo_3-0"><sup><i><b>a</b></i></sup></a> <a href="#cite_ref-Endo_3-1"><sup><i><b>b</b></i></sup></a></span> <span class="reference-text">Jinesh GG, & Kamat AM. <a rel="nofollow" class="external text" href="http://rdcu.be/g8KP">Endocytosis and serpentine filopodia drive blebbishield-mediated resurrection of apoptotic cancer stem cells</a>. Cell Death Discovery 2016 Jan;2: 201569.</span>

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<li id="cite_note-4"><span class="mw-cite-backlink"><b><a href="#cite_ref-4">^</a></b></span> <span class="reference-text">Goodwin Jinesh G, Willis DL, Kamat AM. <a rel="nofollow" class="external text" href="https://www.ncbi.nlm.nih.gov/pubmed/24236543">Bladder cancer stem cells: biological and therapeutic perspectives.</a> Curr Stem Cell Res Ther. 2014 Mar;9(2):89-101.</span>

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<li id="cite_note-auto1-5"><span class="mw-cite-backlink">^ <a href="#cite_ref-auto1_5-0"><sup><i><b>a</b></i></sup></a> <a href="#cite_ref-auto1_5-1"><sup><i><b>b</b></i></sup></a> <a href="#cite_ref-auto1_5-2"><sup><i><b>c</b></i></sup></a></span> <span class="reference-text">Jinesh GG, Molina JM, Huang L, Laing NM, Mills GB, Bar-Eli M & Kamat AM. <a rel="nofollow" class="external text" href="http://rdcu.be/g8KG">Mitochondrial oligomers boost glycolysis in cancer stem cells to facilitate blebbishield-mediated transformation after apoptosis</a>. Cell Death Discovery 2016 Feb;2: 20163.</span>

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<li id="cite_note-6"><span class="mw-cite-backlink"><b><a href="#cite_ref-6">^</a></b></span> <span class="reference-text">Jinesh GG, Rikiya T., Qiang Z., Siddharth G., Kamat AM. <a rel="nofollow" class="external text" href="http://rdcu.be/g8KW">Novel PKC-ζ to p47phox interaction is necessary for transformation from blebbishields</a>. Scientific Reports. 2016 Apr;6:23965.</span>

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<li id="cite_note-7"><span class="mw-cite-backlink"><b><a href="#cite_ref-7">^</a></b></span> <span class="reference-text">Jinesh GG, Laing NM, & Kamat AM. <a rel="nofollow" class="external text" href="http://www.biochemj.org/content/473/1/99.abstract">Smac mimetic with TNF-α targets Pim-1 isoforms and reactive oxygen species production to abrogate transformation from blebbishields</a>. Biochemical Journal 2016 Jan; 473 (1):99-107.</span>

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