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Autophagy and modular restructuring of metabolism control germline tumor differentiation and proliferation in C. elegans.

Gomes LC, Odedra D, Dikic I, Pohl C - Autophagy (2016)

Bottom Line: To understand how autophagy plays this dual role in cancer, in vivo models are required.Fasting of animals with fully developed tumors leads to a doubling of their life span, which depends on modular changes in transcription including switches in transcription factor networks and mitochondrial metabolism.Hence, our results suggest that metabolic restructuring, cell-type specific regulation of autophagy and neuronal differentiation constitute central pathways preventing growth of heterogeneous tumors.

View Article: PubMed Central - PubMed

Affiliation: a Buchmann Institute for Molecular Life Sciences, Goethe University , Frankfurt (Main) , Germany.

ABSTRACT
Autophagy can act either as a tumor suppressor or as a survival mechanism for established tumors. To understand how autophagy plays this dual role in cancer, in vivo models are required. By using a highly heterogeneous C. elegans germline tumor, we show that autophagy-related proteins are expressed in a specific subset of tumor cells, neurons. Inhibition of autophagy impairs neuronal differentiation and increases tumor cell number, resulting in a shorter life span of animals with tumors, while induction of autophagy extends their life span by impairing tumor proliferation. Fasting of animals with fully developed tumors leads to a doubling of their life span, which depends on modular changes in transcription including switches in transcription factor networks and mitochondrial metabolism. Hence, our results suggest that metabolic restructuring, cell-type specific regulation of autophagy and neuronal differentiation constitute central pathways preventing growth of heterogeneous tumors.

No MeSH data available.


Related in: MedlinePlus

Mitochondrial stress signaling is induced during fasting and is required for fasting-induced tumor survival and autophagy. (A) Top left: Changes in transcript levels in regulators implicated in mitochondrial ROS signaling. log2-fold changes between fasting and feeding are shown. Bottom left: Model of mitochondrial ROS signaling. Right: Changes in transcript levels of class II detoxification genes. log2-fold changes between fasting and feeding are shown. (B) Life-span analysis under feeding conditions. Number of animals and Mantel-Cox test P values are shown. (C) Life-span analysis under fasting conditions. Number of animals and Mantel-Cox test P values are shown. (D) Quantification of neuronal differentiation in gld-1 germline tumors with and without NAC. (E) Changes in autophagosomes in control and NAC-treated gld-1 RNAi animals. Left: Representative z-projections of central germline tumor regions. Line scans of greyscale values along the dashed red lines in the projections are shown on the right side of each projection. Scale bar: 10 μm. (F) Quantification of autophagosome numbers; n = 3 animals each; **P ≤ 0.01. (G) Model showing the pathways contributing to tumor cell growth and differentiation. See discussion for details. Scale bar: 10 μm.
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f0009: Mitochondrial stress signaling is induced during fasting and is required for fasting-induced tumor survival and autophagy. (A) Top left: Changes in transcript levels in regulators implicated in mitochondrial ROS signaling. log2-fold changes between fasting and feeding are shown. Bottom left: Model of mitochondrial ROS signaling. Right: Changes in transcript levels of class II detoxification genes. log2-fold changes between fasting and feeding are shown. (B) Life-span analysis under feeding conditions. Number of animals and Mantel-Cox test P values are shown. (C) Life-span analysis under fasting conditions. Number of animals and Mantel-Cox test P values are shown. (D) Quantification of neuronal differentiation in gld-1 germline tumors with and without NAC. (E) Changes in autophagosomes in control and NAC-treated gld-1 RNAi animals. Left: Representative z-projections of central germline tumor regions. Line scans of greyscale values along the dashed red lines in the projections are shown on the right side of each projection. Scale bar: 10 μm. (F) Quantification of autophagosome numbers; n = 3 animals each; **P ≤ 0.01. (G) Model showing the pathways contributing to tumor cell growth and differentiation. See discussion for details. Scale bar: 10 μm.

Mentions: Our analysis reveals that all major pathways leading to mitochondrial catabolism are upregulated in fasted animals, including pathways that lead to anaplerotic reactions for the tricarboxylic acid cycle (Fig. 8E). Activation of these pathways under low glucose supply could lead to activation of AMP-activated protein kinase (aak-2), the main activator of general catabolism, and result in increased reactive oxygen species (ROS) production. Under these conditions, increased ROS levels have been suggested to act as a hormetic stressor, which induces defense mechanisms like phase II detoxification, transduced by a peroxiredoxin (prdx-2), thereby prolonging life span.48,49 Remarkably, activators, transducers and downstream factors of mitochondrial stress signaling are upregulated in germline tumors animals under starvation, including prdx-2 (being part of module 142, Fig. 8D), aak-2, and many components of phase II detoxification (Fig. 9A).49,50Figure 9.


Autophagy and modular restructuring of metabolism control germline tumor differentiation and proliferation in C. elegans.

Gomes LC, Odedra D, Dikic I, Pohl C - Autophagy (2016)

Mitochondrial stress signaling is induced during fasting and is required for fasting-induced tumor survival and autophagy. (A) Top left: Changes in transcript levels in regulators implicated in mitochondrial ROS signaling. log2-fold changes between fasting and feeding are shown. Bottom left: Model of mitochondrial ROS signaling. Right: Changes in transcript levels of class II detoxification genes. log2-fold changes between fasting and feeding are shown. (B) Life-span analysis under feeding conditions. Number of animals and Mantel-Cox test P values are shown. (C) Life-span analysis under fasting conditions. Number of animals and Mantel-Cox test P values are shown. (D) Quantification of neuronal differentiation in gld-1 germline tumors with and without NAC. (E) Changes in autophagosomes in control and NAC-treated gld-1 RNAi animals. Left: Representative z-projections of central germline tumor regions. Line scans of greyscale values along the dashed red lines in the projections are shown on the right side of each projection. Scale bar: 10 μm. (F) Quantification of autophagosome numbers; n = 3 animals each; **P ≤ 0.01. (G) Model showing the pathways contributing to tumor cell growth and differentiation. See discussion for details. Scale bar: 10 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4835962&req=5

f0009: Mitochondrial stress signaling is induced during fasting and is required for fasting-induced tumor survival and autophagy. (A) Top left: Changes in transcript levels in regulators implicated in mitochondrial ROS signaling. log2-fold changes between fasting and feeding are shown. Bottom left: Model of mitochondrial ROS signaling. Right: Changes in transcript levels of class II detoxification genes. log2-fold changes between fasting and feeding are shown. (B) Life-span analysis under feeding conditions. Number of animals and Mantel-Cox test P values are shown. (C) Life-span analysis under fasting conditions. Number of animals and Mantel-Cox test P values are shown. (D) Quantification of neuronal differentiation in gld-1 germline tumors with and without NAC. (E) Changes in autophagosomes in control and NAC-treated gld-1 RNAi animals. Left: Representative z-projections of central germline tumor regions. Line scans of greyscale values along the dashed red lines in the projections are shown on the right side of each projection. Scale bar: 10 μm. (F) Quantification of autophagosome numbers; n = 3 animals each; **P ≤ 0.01. (G) Model showing the pathways contributing to tumor cell growth and differentiation. See discussion for details. Scale bar: 10 μm.
Mentions: Our analysis reveals that all major pathways leading to mitochondrial catabolism are upregulated in fasted animals, including pathways that lead to anaplerotic reactions for the tricarboxylic acid cycle (Fig. 8E). Activation of these pathways under low glucose supply could lead to activation of AMP-activated protein kinase (aak-2), the main activator of general catabolism, and result in increased reactive oxygen species (ROS) production. Under these conditions, increased ROS levels have been suggested to act as a hormetic stressor, which induces defense mechanisms like phase II detoxification, transduced by a peroxiredoxin (prdx-2), thereby prolonging life span.48,49 Remarkably, activators, transducers and downstream factors of mitochondrial stress signaling are upregulated in germline tumors animals under starvation, including prdx-2 (being part of module 142, Fig. 8D), aak-2, and many components of phase II detoxification (Fig. 9A).49,50Figure 9.

Bottom Line: To understand how autophagy plays this dual role in cancer, in vivo models are required.Fasting of animals with fully developed tumors leads to a doubling of their life span, which depends on modular changes in transcription including switches in transcription factor networks and mitochondrial metabolism.Hence, our results suggest that metabolic restructuring, cell-type specific regulation of autophagy and neuronal differentiation constitute central pathways preventing growth of heterogeneous tumors.

View Article: PubMed Central - PubMed

Affiliation: a Buchmann Institute for Molecular Life Sciences, Goethe University , Frankfurt (Main) , Germany.

ABSTRACT
Autophagy can act either as a tumor suppressor or as a survival mechanism for established tumors. To understand how autophagy plays this dual role in cancer, in vivo models are required. By using a highly heterogeneous C. elegans germline tumor, we show that autophagy-related proteins are expressed in a specific subset of tumor cells, neurons. Inhibition of autophagy impairs neuronal differentiation and increases tumor cell number, resulting in a shorter life span of animals with tumors, while induction of autophagy extends their life span by impairing tumor proliferation. Fasting of animals with fully developed tumors leads to a doubling of their life span, which depends on modular changes in transcription including switches in transcription factor networks and mitochondrial metabolism. Hence, our results suggest that metabolic restructuring, cell-type specific regulation of autophagy and neuronal differentiation constitute central pathways preventing growth of heterogeneous tumors.

No MeSH data available.


Related in: MedlinePlus