Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

Chaabane, Wiem; User, Sırma Damla; El-Gazzah, M.; Jaksik, Roman; Sajjadi, Elaheh; Rzeszowska-Wolny, Joanna; Łos, Marek

doi:10.1007/s00005-012-0205-y

Cited by 252 publications

(161 citation statements)

References 137 publications

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“…Cell death in general occurs by apoptotic, necrotic, autophagic, or additional mixed mechanisms (39). Like the extensive degeneration of PNs in young nr-mutant mice, we found selective death of PNs in P20 tPA-injected WT cerebella ( Fig.…”

Section: Cell Death Caused By Excess Tpa Via Abnormal Mitochondria Andsupporting

confidence: 53%

Tissue plasminogen activator regulates Purkinje neuron development and survival

Li¹,

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The cerebellar cortex is centrally involved in motor coordination and learning, and its sole output is provided by Purkinje neurons (PNs). Growth of PN dendrites and their major synaptic input from granule cell parallel fiber axons takes place almost entirely in the first several postnatal weeks. PNs are more vulnerable to cell death than most other neurons, but the mechanisms remain unclear. We find that the homozygous nervous (nr) mutant mouse's 10-fold-increased cerebellar tissue plasminogen activator (tPA), a part of the tPA/plasmin proteolytic system, influences several different molecular mechanisms, each regulating a key aspect of postnatal PN development, followed by selective PN necrosis, as follows. (i) Excess endogenous or exogenous tPA inhibits dendritic growth in vivo and in vitro by activating protein kinase Cγ and phosphorylation of microtubule-associated protein 2. (ii) tPA/plasmin proteolysis impairs parallel fiber-PN synaptogenesis by blocking brain-derived neurotrophic factor/tyrosine kinase receptor B signaling. (iii) Voltage-dependent anion channel 1 (a mitochondrial and plasma membrane protein) bound with kringle 5 (a peptide derived from the excess plasminogen) promotes pathological enlargement and rounding of PN mitochondria, reduces mitochondrial membrane potential, and damages plasma membranes. These abnormalities culminate in young nr PN necrosis that can be mimicked in wild-type PNs by exogenous tPA injection into cerebellum or prevented by endogenous tPA deletion in nr:tPA-knockout double mutants. In sum, excess tPA/plasmin, through separate downstream molecular mechanisms, regulates postnatal PN dendritogenesis, synaptogenesis, mitochondrial structure and function, and selective PN viability. plasma membrane integrity | postnatal development | spinocerebellar ataxia | synaptic ultrastructure

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Section: Cell Death Caused By Excess Tpa Via Abnormal Mitochondria Andsupporting

confidence: 53%

Tissue plasminogen activator regulates Purkinje neuron development and survival

Li¹,

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…42,43 The mTOR pathway can form 2 multiprotein complexes with distinct functionalities: mTORC1 (leads to Akt inhibition) and mTORC2 (leads to Akt activation). Phoshorylated Akt induces mTORC1 activation through intermediate molecules and Akt itself is phoshorylated by the mTORC2 complex.…”

Section: Discussionmentioning

confidence: 99%

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1

et al. 2015

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Cancer stem-like cells (CSCs) are a rare subpopulation of cancer cells capable of propagating the disease and causing cancer recurrence. In this study, we found that the cellular localization of PKB/Akt kinase affects the maintenance of CSCs. When Akt tagged with nuclear localization signal (Akt-NLS) was overexpressed in SKBR3 and MDA-MB468 cells, these cells showed a 10-15% increase in the number of cells with CSCs enhanced ALDH activity and demonstrated a CD44 CHigh /CD24 ¡Low phenotype. This effect was completely reversed in the presence of Aktspecific inhibitor, triciribine. Furthermore, cells overexpressing Akt or Akt-NLS were less likely to be in G0/G1 phase of the cell cycle by inactivating p21 Waf1/Cip1 and exhibited increased clonogenicity and proliferation as assayed by colony-forming assay (mammosphere formation). Thus, our data emphasize the importance the intracellular localization of Akt has on stemness in human breast cancer cells. It also indicates a new robust way for improving the enrichment and culture of CSCs for experimental purposes. Hence, it allows for the development of simpler protocols to study stemness, clonogenic potency, and screening of new chemotherapeutic agents that preferentially target cancer stem cells. Summary: The presented data, (i) shows new, stemness-promoting role of nuclear Akt/PKB kinase, (ii) it underlines the effects of nuclear Akt on cell cycle regulation, and finally (iii) it suggests new ways to study cancer stem-like cells.

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“…We found that free CQ significantly increased LC3-II expression in A549/T and A2780/T cells in a concentration-dependent manner, and this inhibition effect also occurred when CQ was co-encapsulated with PTX in liposomes ( Figure 5). Therefore, liposomal CQ could still act as a sensitizer to enhance PTX-induced apoptosis 36,37 and cytotoxicity in A549/T and A2780/T cells ( Figure 2; Table 2). These results show that A549/T cells were more sensitive to the treatment with PCL preparations compared to A2780/T cells.…”

Section: Discussionmentioning

confidence: 99%

Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes

Gao¹,

Xu²,

Qiu³

2015

IJN

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A novel composite liposomal system co-encapsulating paclitaxel (PTX) with chloroquine phosphate (CQ) was designed for treating PTX-resistant carcinoma. It was confirmed that liposomal CQ can sensitize PTX by means of autophagy inhibition and competitively binding with multidrug-resistance transporters. Furthermore, according to the in vitro cytotoxicity and apoptosis assay, real-time observation of cellular uptake, and in vivo tissue distribution study, co-encapsulation of PTX and CQ in liposomes was validated as superior to the mixture of PTX liposome plus CQ liposome due to the simultaneous delivery and synergetic effect of the two drugs. Consequently, this composite liposome achieved significantly stronger anticancer efficacy in vivo than the PTX liposome plus CQ liposome mixture. This study helps to guide and enlighten ongoing and future clinical trials about the optimal administration modes for drug combination therapy.

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Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

Abstract: Cell death is a fundamental ingredient of life.

Cited by 252 publications

References 137 publications

Tissue plasminogen activator regulates Purkinje neuron development and survival

Tissue plasminogen activator regulates Purkinje neuron development and survival

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1

Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes

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Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

Abstract: Cell death is a fundamental ingredient of life.

Cited by 252 publications

References 137 publications

Tissue plasminogen activator regulates Purkinje neuron development and survival

Tissue plasminogen activator regulates Purkinje neuron development and survival

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21Waf1/Cip1and p27kip1

Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes

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Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1