Caspase-8 Induces Lysosome-Associated Cell Death in Cancer Cells.

07:00 EST 21st January 2020 | BioPortfolio

Summary of "Caspase-8 Induces Lysosome-Associated Cell Death in Cancer Cells."

Caspase-8, a well-characterized initiator of apoptosis, has also been found to play non-apoptotic roles in cells. In this study, we reveal that caspase-8 can induce cell death in a special way, which does not depend on activation of caspases and mitochondrial initiation. Instead, we prove that caspase-8 can cause lysosomal deacidification and thus lysosomal membrane permeabilization. V-ATPase is a multi-subunit proton pump that acidifies the lumen of lysosome. Our results demonstrate that caspase-8 can bind to the V domain of lysosomal Vacuolar H-ATPase (V-ATPase), but not the V domain, to block the assembly of functional V-ATPase and alkalinize lysosomes. We further demonstrate that the C-terminal of caspase-8 is mainly responsible for the interaction with V-ATPase and can suffice to inhibit survival of cancer cells. Interestingly, regardless of the protein level, it is the expression rate of caspase-8 that is the major cause of cell death. Taken together, we identify a previously unrevealed caspase-8-mediated cell death pathway different form typical apoptosis, which could render caspase-8 a particular physiological function and may be potentially applied in treatments for apoptosis-resistant cancers.


Journal Details

This article was published in the following journal.

Name: Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024


DeepDyve research library

PubMed Articles [37299 Associated PubMed Articles listed on BioPortfolio]

Lupiwighteone induces caspase-dependent and -independent apoptosis on human breast cancer cells via inhibiting PI3K/Akt/mTOR pathway.

Breast cancer is one of the most common causes of mortality in women. Lupiwighteone has anticancer effects in prostate cancer cells and neuroblastoma cells. However, the molecular and cellular mechani...

Sanggenol L promotes apoptotic cell death in melanoma skin cancer cells through activation of caspase cascades and apoptosis-inducing factor.

Sanggenol L is one component of root bark of Morus alba. The molecular and cellular mechanisms of sanggenol L effects on melanoma cells are not well known. Recently, melanoma is the most common skin c...

Concomitant targeting of Hedgehog signaling and MCL-1 synergistically induces cell death in Hedgehog-driven cancer cells.

In the present study, we show that concomitant inhibition of Hedgehog (HH) signaling by the Glioma-Associated Oncogene Homolog1 (GLI1)-targeting agent GANT61 and the antiapoptotic BCL-2 protein family...

Cancer Cells Employ Nuclear Caspase-8 to Overcome the p53-Dependent G2/M Checkpoint through Cleavage of USP28.

Cytosolic caspase-8 is a mediator of death receptor signaling. While caspase-8 expression is lost in some tumors, it is increased in others, indicating a conditional pro-survival function of caspase-8...

Oxyresveratrol drives caspase-independent apoptosis-like cell death in MDA-MB-231 breast cancer cells through the induction of ROS.

Earlier studies from our laboratory have demonstrated that Oxyresveratrol (OXY), a hydroxyl-substituted stilbene, exhibits potent inhibition of human melanoma cell proliferation. The present study def...

Clinical Trials [28193 Associated Clinical Trials listed on BioPortfolio]

Analysis of the Variation in Caspase-8 Availability and Cleavage in Oral Squamous Cell Carcinoma

Control of cell death is frequently disrupted in cancer resulting in overgrowth of tumour cells. Caspase-8 is a key enzyme involved in controlling cell death. This study examines the impor...

Characterization of Non-canonical Way in Inflammasome Monocytes of Patients With Severe Sepsis

Activation of caspase-4 and human caspase-5 (orthologs of caspase-11 in mice) in innate immune cells.

LBH589 (Panobinostat) for the Treatment of Myelofibrosis

LBH589 is an oral drug that targets the myelofibrosis cells in the bone marrow and induces cell death by allowing for the expression of certain suppressed genes that are important in regul...

Evaluation of PD1 / PDL1 Expression on Blood Cells & Tumor Tissue, Their Role as a Prognostic Target in NSCLC Patients

Several reports have examined Programmed Death 1 (PD-1) expression on tumor-infiltrating T-cells, and its correlation with prognosis has been discussed. However, Programmed Death 1 (PD1)/P...

A Phase I, Open-Labeled, Single-Arm, Dose Escalation, Clinical and Pharmacology Study of Dichloroacetate (DCA) in Patients With Recurrent and/or Metastatic Solid Tumours

Dichloroacetate (DCA) is a small molecule that has been used for years to treat lactic acidosis and rare metabolic disorders in humans. Further testing now shows that it may suppress the ...

Medical and Biotech [MESH] Definitions

A long pro-domain caspase that contains a death effector domain in its pro-domain region. Caspase 8 plays a role in APOPTOSIS by cleaving and activating EFFECTOR CASPASES. Activation of this enzyme can occur via the interaction of its N-terminal death effector domain with DEATH DOMAIN RECEPTOR SIGNALING ADAPTOR PROTEINS.

A long pro-domain caspase that contains a death effector domain in its pro-domain region. Activation of this enzyme can occur via the interaction of its N-terminal death effector domain with DEATH DOMAIN RECEPTOR SIGNALING ADAPTOR PROTEINS. Caspase 10 plays a role in APOPTOSIS by cleaving and activating EFFECTOR CASPASES. Several isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.

A signal-transducing adaptor protein that associates with TNF RECEPTOR complexes. It contains a death effector domain that can interact with death effector domains found on INITIATOR CASPASES such as CASPASE 8 and CASPASE 10. Activation of CASPASES via interaction with this protein plays a role in the signaling cascade that leads to APOPTOSIS.

A death domain receptor signaling adaptor protein that plays a role in signaling the activation of INITIATOR CASPASES such as CASPASE 2. It contains a death domain that is specific for RIP SERINE-THEONINE KINASES and a caspase-binding domain that binds to and activates CASPASES such as CASPASE 2.

An inhibitory T-lymphocyte receptor that has specificity for CD274 ANTIGEN and PROGRAMMED CELL DEATH 1 LIGAND 2 PROTEIN. Signaling by the receptor limits T cell proliferation and INTERFERON GAMMA synthesis. The receptor also may play an essential role in the regulatory pathway that induces PERIPHERAL TOLERANCE.

Quick Search

DeepDyve research library

Relevant Topic

  Bladder Cancer Brain Cancer Breast Cancer Cancer Cervical Cancer Colorectal Head & Neck Cancers Hodgkin Lymphoma Leukemia Lung Cancer Melanoma Myeloma Ovarian Cancer Pancreatic Cancer ...

Searches Linking to this Article