Autophagy and Cancer Drug Discovery

  • Hua Yang
  • Jessica A. Williams
  • Yifeng Hou
  • Menghang Xia
  • Ying-Hong Shi
  • Jia Fan
  • Wen-Xing Ding
Chapter
Part of the Current Cancer Research book series (CUCR, volume 8)

Abstract

Autophagy is a highly conserved lysosomal degradation pathway that is important for maintaining cellular homeostasis by degrading bulk cytoplasm and superfluous or damaged organelles. Autophagy plays a dual role in cancer because it suppresses tumorigenesis and also promotes cancer cell survival for existing tumors. Therefore, targeting autophagy has become a promising therapeutic approach for preventing or treating cancers. With the rapid progression of autophagy research and our expanding knowledge on autophagy machinery and regulation pathways, many high-throughput screening assays have been established and conducted. Here, we summarize potential autophagy proteins and signaling pathways that could be drug targets for modulating autophagy. We also summarize novel compounds that have been discovered from high-throughput screening, which can either inhibit or promote autophagy.

Keywords

Autophagy Drug Cancer Diseases GFP-LC3 Screen AMPK mTOR PI3K Bcl-2 Cell death Transcription factor FoxO TFEB 

Abbreviations

3-MA

3-Methyladenine

4EBP1

4E-binding protein 1

AMP

Adenosine monophosphate

AMPK

5′ Adenosine monophosphate-activated protein kinase

Atg

Autophagy-related

ATM

Ataxia telangiectasia mutated

ATP

Adenosine-5′-triphosphate

BiFC–FRET

Bimolecular fluorescence complementation–fluorescence ­resonance energy transfer

CaMKKs

Calmodulin-dependent protein kinase kinases

DAPK1

Death-associated protein kinase 1

eIF4E

Eukaryotic translation initiation factor 4E

FACS

Fluorescence-activated cell sorter

FEZ1

Fasciculation and elongation protein zeta-1

FoxO

Forkhead box transcription factor class O

FRET

Fluorescence resonance energy transfer

GFP

Green fluorescent protein

GPCRs

G-protein-coupled receptors

HCQ

Hydroxychloroquine

IAV

Influenza A virus

IRS

Insulin receptor substrate

Jak3

Janus 3 kinase

LKB1

Liver kinase B1

MEF

Mouse embryonic fibroblasts

mLST8

Target of rapamycin complex subunit LST8

mTOR

Mammalian target of rapamycin

mTORC1

mTOR complex 1

mTORC2

mTOR complex 2

NF-kappaB

Nuclear factor-kappaB

Nrf2

Nuclear factor (erythroid-derived 2)-like 2

p19ARF

p19 Alternative reading frame

p70S6K1

p70 Ribosomal protein S6 kinase 1

PDK

Phosphoinositide-dependent protein kinase

PE

Phosphatidylethanolamine

PI3K

Phosphatidylinositol 3-kinase

PIP2

Phosphatidylinositol 4,5-bisphosphate

PIP3

Phosphatidylinositol 3,4,5-trisphosphate

PKB

Protein kinase B

PKC

Protein kinase C

PLA2

Phospholipase A2

PPAR-γ

Peroxisome proliferator-activated receptor γ

PTEN

Phosphatase and tensin homolog

Raptor

Regulatory associated protein of mTOR

RFP

Red fluorescence protein

Rheb

Ras homolog enriched in brain

Rictor

Rapamycin-insensitive companion of mTOR

RLuc

Renilla Reinformis luciferase

RTK

Receptor tyrosine kinase

SCOC

Short coiled-coil protein

SGK

Serum- and glucocorticoid-induced protein kinase

SREBP1/2

Sterol regulatory element-binding protein1/2

TAK1

Transforming growth factor-β-activated kinase-1

TFEB

Transcriptional factor EB

TSC

Tuberous sclerosis complex

Notes

Acknowledgements

The research work in W.X. Ding’s lab was supported in part by the NIAAA funds R01 AA020518-01, R21 AA017421, National Center for Research Resources (5P20RR021940-07), and P20 RR016475 from the IDeA Networks of Biomedical Research Excellence (INBRE) program of the National Center for Research Resources. J.A. Williams was supported by the “Training Program in Environmental Toxicology” (grant 5 T32 ES007079) from the National Institute of Environmental Health Sciences. Y.F. Hou was supported by National Natural Science Foundation of China (Contract grant numbers: 81072165), and the Shanghai Science and Technology Committee (Contract grant numbers: 09PJ1402700). The authors would like to thank Bonnie Goodwin for technical support of ArrayScan.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Hua Yang
    • 1
    • 2
  • Jessica A. Williams
    • 1
  • Yifeng Hou
    • 3
  • Menghang Xia
    • 4
  • Ying-Hong Shi
    • 2
  • Jia Fan
    • 2
  • Wen-Xing Ding
    • 1
  1. 1.Department of Pharmacology, Toxicology and TherapeuticsThe University of Kansas Medical CenterKansas CityUSA
  2. 2.Department of Liver Surgery, Liver Cancer Institute, Zongshan HospitalFudan UniversityShanghaiChina
  3. 3.Department of Breast Surgery, Breast Cancer Institute, Cancer HospitalFudan UniversityShanghaiChina
  4. 4.National Center for Advancing Translational Sciences, National Institutes of HealthBethesdaUSA

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