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Techniques to Induce and Quantify Cellular Senescence
Published on: May 1, 2017
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A hydride transfer complex reprograms NAD metabolism and bypasses senescence
Sebastian Igelmann1, Frédéric Lessard2, Oro Uchenunu3
1CRCHUM, 900 Saint-Denis St, Montréal, QC H2X 0A9, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
Molecular Cell
|September 21, 2021
Summary
A newly discovered hydride transfer complex (HTC) reprograms NAD metabolism, enabling cancer cells to bypass cellular senescence. This complex is repressed in senescent cells but induced by p53 inactivation.
Area of Science:
- Biochemistry
- Cell Biology
- Cancer Research
Background:
- Metabolic reprogramming and redox balance are crucial in cancer development.
- Cellular senescence acts as a tumor-suppressive mechanism often bypassed during tumorigenesis.
- The mechanisms by which cancer cells circumvent senescence are not fully understood.
Purpose of the Study:
- To identify and characterize a novel multi-enzymatic complex involved in metabolic reprogramming.
- To investigate the role of this complex in overcoming cellular senescence.
- To explore its potential implications in cancer progression.
Main Methods:
- Recombinant protein expression and in vitro assembly of the hydride transfer complex (HTC).
- Analysis of HTC localization in phase-separated bodies within cancer and hypoxic cells.
- Investigation of HTC regulation by p53 inactivation and its impact on cellular senescence.
- Assessment of HTC enzyme expression in prostate cancer models and its effect on senescence induction.
- Functional studies involving exogenous HTC expression to bypass senescence and cooperate with oncogenic RAS.
Main Results:
- A novel multi-enzymatic complex (HTC), comprising malate dehydrogenase 1, malic enzyme 1, and cytosolic pyruvate carboxylase, was identified.
- HTC facilitates the transfer of reducing equivalents from NADH to NADP+, reprogramming NAD metabolism.
- HTC is localized in cytosolic phase-separated bodies in cancer and hypoxic cells.
- HTC is repressed in senescent cells but induced upon p53 inactivation.
- HTC enzymes are upregulated in prostate cancer models, and their inactivation induces senescence.
- Exogenous HTC expression bypasses senescence, confers resistance to complex I inhibitors, and cooperates with oncogenic RAS.
Conclusions:
- A novel hydride transfer complex (HTC) has been discovered that significantly reprograms cellular metabolism.
- This complex plays a critical role in enabling cancer cells to overcome the barrier of cellular senescence.
- The findings provide new insights into metabolic adaptations that promote tumorigenesis and offer potential therapeutic targets.
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