# Non-canonical Caspase-8 Activation on Autophagosomal Membranes

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2022 · $341,436

## Abstract

Project Summary/Abstract
 The goal of this project is to test the hypothesis that an accumulation of immature autophagosomal
membranes induces the non-canonical activation of caspase-8 to switch cytoprotective autophagy to apoptosis
for a novel anti-cancer strategy. Autophagy is a double-edged sword in cancer as it can either suppress
oncogenesis or promote cancer cell survival. The lack of selective inhibitors of autophagic flux has made it
difficult to determine if inhibition of autophagy is a valid cancer strategy. We, and others, have demonstrated that
autophagosomal membranes can serve as platforms for an intracellular death-inducing signaling complex
(iDISC) that activates caspase-8 independent of death receptor signaling. Mechanistically, the iDISC recruits
pro-caspase-8 to autophagosomal membranes by two arms: 1) ATG12-ATG5: FADD: caspase-8; and 2) LC3-II:
p62: caspase-8. As ATG12-ATG5 dissociates from the phagophore upon membrane closure and sealed
autophagosomes traffic to lysosomes for degradation, we hypothesize that inhibition of phagophore closure will
stabilize iDISC assembly for caspase-8 activation. Indeed, our preliminary data reveal that cells deficient in
ATG2A/B or VMP1, two regulators of phagophore closure, accumulate immature phagophores that promote
iDISC-mediated caspase-8 activation. We propose that elucidation of the molecular mechanisms of phagophore
closure will lead to more selective targets for autophagy inhibition and present novel opportunities for cancer
therapy. We will investigate our hypothesis in the following specific aims: 1) to demonstrate that the accumulation
of immature phagophores initiates iDISC-mediated caspase-8 activation and characterize molecular regulators
of non-canonical caspase-8 activation; 2) to test the hypothesis that ATG2A/B and VMP1 regulate phagophore
closure through the delivery of ATG9-containing membranes; 3) to demonstrate that impaired phagophore
closure can switch autophagy to iDISC-mediated apoptosis in vivo for the suppression of pediatric acute myeloid
leukemia (AML) with MLL (mixed lineage leukemia) gene rearrangements.

## Key facts

- **NIH application ID:** 10448458
- **Project number:** 5R01CA222349-05
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** HONG-GANG WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $341,436
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448458

## Citation

> US National Institutes of Health, RePORTER application 10448458, Non-canonical Caspase-8 Activation on Autophagosomal Membranes (5R01CA222349-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10448458. Licensed CC0.

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