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Updated: May 27, 2025
Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
Inactivation of necroptosis-promoting protein MLKL creates a therapeutic vulnerability in colorectal cancer cells
Peijia Jiang1, Sandhya Chipurupalli1, Byong Hoon Yoo1
1Departments of Pediatrics & Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada.
Abstract:
Mortality from colorectal cancer (CRC) is significant, and novel CRC therapies are needed. A pseudokinase MLKL typically executes necroptotic cell death, and MLKL inactivation protects cells from such death. However, we found unexpectedly that MLKL gene knockout enhanced CRC cell death caused by a protein synthesis inhibitor homoharringtonine used for chronic myeloid leukemia treatment. In an effort to explain this finding, we observed that MLKL gene knockout reduces the basal CRC cell autophagy and renders such autophagy critically dependent on the presence of VPS37A, a component of the ESCRT-I complex. We further found that the reason why homoharringtonine enhances CRC cell death caused by MLKL gene knockout is that homoharringtonine activates p38 MAP kinase and thereby prevents VPS37A from supporting autophagy in MLKL-deficient cells. We observed that the resulting inhibition of the basal autophagy in CRC cells triggers their parthanatos, a cell death type driven by poly(ADP-ribose) polymerase hyperactivation. Finally, we discovered that a pharmacological MLKL inhibitor necrosulfonamide strongly cooperates with homoharringtonine in suppressing CRC cell tumorigenicity in mice. Thus, while MLKL promotes cell death during necroptosis, MLKL supports the basal autophagy in CRC cells and thereby protects them from death. MLKL inactivation reduces such autophagy and renders the cells sensitive to autophagy inhibitors, such as homoharringtonine. Hence, MLKL inhibition creates a therapeutic vulnerability that could be utilized for CRC treatment.
Insights
MLKL inhibition unexpectedly enhances colorectal cancer cell death by blocking autophagy. This creates a new therapeutic vulnerability, as MLKL inhibitors combined with homoharringtonine suppress tumor growth.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Colorectal cancer (CRC) poses a significant mortality risk, necessitating novel therapeutic strategies.
- The pseudokinase MLKL is known to mediate necroptotic cell death, with its inactivation typically conferring protection.
- Unexpectedly, MLKL inactivation was found to sensitize CRC cells to certain treatments.
Purpose of the Study:
- To investigate the unexpected finding that MLKL gene knockout enhances CRC cell death induced by homoharringtonine.
- To elucidate the underlying molecular mechanisms connecting MLKL, autophagy, and cell death in CRC.
- To explore the therapeutic potential of targeting MLKL in combination with existing drugs for CRC treatment.
Main Methods:
- Utilized MLKL gene knockout in colorectal cancer cells.
- Investigated the role of autophagy and its dependence on VPS37A in MLKL-deficient cells.
- Examined the effects of homoharringtonine and p38 MAP kinase activation on autophagy.
- Assessed cell death pathways, including parthanatos.
- Evaluated the synergistic effect of MLKL inhibitor necrosulfonamide and homoharringtonine in a mouse model of CRC.
Main Results:
- MLKL gene knockout reduced basal autophagy in CRC cells, making it dependent on VPS37A.
- Homoharringtonine activated p38 MAP kinase, inhibiting VPS37A-mediated autophagy in MLKL-deficient cells.
- Inhibition of autophagy triggered parthanatos, a form of cell death, in MLKL-deficient CRC cells.
- Pharmacological MLKL inhibition (necrosulfonamide) synergized with homoharringtonine to suppress CRC cell tumorigenicity in vivo.
Conclusions:
- MLKL plays a protective role in CRC by supporting basal autophagy, contrary to its role in necroptosis.
- MLKL inactivation creates a therapeutic vulnerability by sensitizing CRC cells to autophagy inhibitors.
- Combining MLKL inhibitors with agents like homoharringtonine presents a promising strategy for colorectal cancer treatment.
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