Rab25 increases cellular ATP and glycogen stores protecting cancer cells from bioenergetic stress

Kwai Wa Cheng, Roshan Agarwal, Shreya Mitra, Ju Seog Lee, Mark Carey, Joe Gray, Gordon Mills

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Cancer cells are metabolically stressed during tumour progression due to limited tumour vascularity and resultant nutrient, growth factor and oxygen deficiency that can induce cell death and inhibit tumour growth. We demonstrate that Rab25, a small GTPase involved in endosomal recycling, that is genomically amplified in multiple tumour lineages, is a key regulator of cellular bioenergetics and autophagy. RAB25 enhanced survival during nutrient stress by preventing apoptosis and autophagy via binding and activating AKT leading to increased glucose uptake and improved cellular bioenergetics. Unexpectedly, Rab25 induced the accumulation of glycogen in epithelial cancer cells, a process not previously identified. Strikingly, an increase in basal ATP levels combined with AKT-dependent increases in glucose uptake and glycogen storage allowed maintenance of ATP levels during bioenergetic stress. The clinical relevance of these findings was validated by the ability of a Rab25-dependent expression profile enriched for bioenergetics targets to identify patients with a poor prognosis. Thus, Rab25 is an unexpected regulator of cellular bioenergetics implicated as a useful biomarker and potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)125-141
Number of pages17
JournalEMBO Molecular Medicine
Volume4
Issue number2
DOIs
StatePublished - Feb 2012
Externally publishedYes

Fingerprint

Glycogen
Energy Metabolism
Adenosine Triphosphate
Neoplasms
Autophagy
Glucose
Food
Monomeric GTP-Binding Proteins
Intercellular Signaling Peptides and Proteins
Cell Death
Biomarkers
Epithelial Cells
Maintenance
Apoptosis
Survival
Growth

Keywords

  • AKT
  • Bioenergetic
  • Cell death
  • Glycogen
  • Rab25

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Rab25 increases cellular ATP and glycogen stores protecting cancer cells from bioenergetic stress. / Cheng, Kwai Wa; Agarwal, Roshan; Mitra, Shreya; Lee, Ju Seog; Carey, Mark; Gray, Joe; Mills, Gordon.

In: EMBO Molecular Medicine, Vol. 4, No. 2, 02.2012, p. 125-141.

Research output: Contribution to journalArticle

Cheng, Kwai Wa ; Agarwal, Roshan ; Mitra, Shreya ; Lee, Ju Seog ; Carey, Mark ; Gray, Joe ; Mills, Gordon. / Rab25 increases cellular ATP and glycogen stores protecting cancer cells from bioenergetic stress. In: EMBO Molecular Medicine. 2012 ; Vol. 4, No. 2. pp. 125-141.
@article{7989d418b28345a5b5ab1dd7ee73fed9,
title = "Rab25 increases cellular ATP and glycogen stores protecting cancer cells from bioenergetic stress",
abstract = "Cancer cells are metabolically stressed during tumour progression due to limited tumour vascularity and resultant nutrient, growth factor and oxygen deficiency that can induce cell death and inhibit tumour growth. We demonstrate that Rab25, a small GTPase involved in endosomal recycling, that is genomically amplified in multiple tumour lineages, is a key regulator of cellular bioenergetics and autophagy. RAB25 enhanced survival during nutrient stress by preventing apoptosis and autophagy via binding and activating AKT leading to increased glucose uptake and improved cellular bioenergetics. Unexpectedly, Rab25 induced the accumulation of glycogen in epithelial cancer cells, a process not previously identified. Strikingly, an increase in basal ATP levels combined with AKT-dependent increases in glucose uptake and glycogen storage allowed maintenance of ATP levels during bioenergetic stress. The clinical relevance of these findings was validated by the ability of a Rab25-dependent expression profile enriched for bioenergetics targets to identify patients with a poor prognosis. Thus, Rab25 is an unexpected regulator of cellular bioenergetics implicated as a useful biomarker and potential therapeutic target.",
keywords = "AKT, Bioenergetic, Cell death, Glycogen, Rab25",
author = "Cheng, {Kwai Wa} and Roshan Agarwal and Shreya Mitra and Lee, {Ju Seog} and Mark Carey and Joe Gray and Gordon Mills",
year = "2012",
month = "2",
doi = "10.1002/emmm.201100193",
language = "English (US)",
volume = "4",
pages = "125--141",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Rab25 increases cellular ATP and glycogen stores protecting cancer cells from bioenergetic stress

AU - Cheng, Kwai Wa

AU - Agarwal, Roshan

AU - Mitra, Shreya

AU - Lee, Ju Seog

AU - Carey, Mark

AU - Gray, Joe

AU - Mills, Gordon

PY - 2012/2

Y1 - 2012/2

N2 - Cancer cells are metabolically stressed during tumour progression due to limited tumour vascularity and resultant nutrient, growth factor and oxygen deficiency that can induce cell death and inhibit tumour growth. We demonstrate that Rab25, a small GTPase involved in endosomal recycling, that is genomically amplified in multiple tumour lineages, is a key regulator of cellular bioenergetics and autophagy. RAB25 enhanced survival during nutrient stress by preventing apoptosis and autophagy via binding and activating AKT leading to increased glucose uptake and improved cellular bioenergetics. Unexpectedly, Rab25 induced the accumulation of glycogen in epithelial cancer cells, a process not previously identified. Strikingly, an increase in basal ATP levels combined with AKT-dependent increases in glucose uptake and glycogen storage allowed maintenance of ATP levels during bioenergetic stress. The clinical relevance of these findings was validated by the ability of a Rab25-dependent expression profile enriched for bioenergetics targets to identify patients with a poor prognosis. Thus, Rab25 is an unexpected regulator of cellular bioenergetics implicated as a useful biomarker and potential therapeutic target.

AB - Cancer cells are metabolically stressed during tumour progression due to limited tumour vascularity and resultant nutrient, growth factor and oxygen deficiency that can induce cell death and inhibit tumour growth. We demonstrate that Rab25, a small GTPase involved in endosomal recycling, that is genomically amplified in multiple tumour lineages, is a key regulator of cellular bioenergetics and autophagy. RAB25 enhanced survival during nutrient stress by preventing apoptosis and autophagy via binding and activating AKT leading to increased glucose uptake and improved cellular bioenergetics. Unexpectedly, Rab25 induced the accumulation of glycogen in epithelial cancer cells, a process not previously identified. Strikingly, an increase in basal ATP levels combined with AKT-dependent increases in glucose uptake and glycogen storage allowed maintenance of ATP levels during bioenergetic stress. The clinical relevance of these findings was validated by the ability of a Rab25-dependent expression profile enriched for bioenergetics targets to identify patients with a poor prognosis. Thus, Rab25 is an unexpected regulator of cellular bioenergetics implicated as a useful biomarker and potential therapeutic target.

KW - AKT

KW - Bioenergetic

KW - Cell death

KW - Glycogen

KW - Rab25

UR - http://www.scopus.com/inward/record.url?scp=84863033816&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863033816&partnerID=8YFLogxK

U2 - 10.1002/emmm.201100193

DO - 10.1002/emmm.201100193

M3 - Article

C2 - 22253197

AN - SCOPUS:84863033816

VL - 4

SP - 125

EP - 141

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

IS - 2

ER -