Mitochondria supply energy for cellular function while their dysfunction causes cell death. Endoplasmic reticulum (ER) mediates protein synthesis and folding and its dysfunction causes ER stress and protein aggregation. Autophagy is activated to clean up defective mitochondria and protein aggregates (aggresomes) through lysosomes to maintain mitochondrial homeostasis and relieve ER stress. Autophagic dysfunction induces oxidative stress that causes DNA double strand breaks and the generation of aneuploidy cells leading to cancers. We discovered that C19ORF5 regulates general autophagy and mitotic mitophagy in collaboration with tumor suppressor RASSF1A-mediated microtubular dynamics and overall autophagic activity via Bcl-2/XL protein-controlled canonical and noncanonical autophagic pathways. We predict that C19ORF5 inhibits the generation of aneuploidy to prevent cancer at its origin and impedes further karyotype evolution that underlies cancer's variability and relapse after therapy. To test the hypothesis, specific aims are designed to characterize (1) the mechanism by which C19ORF5 regulates autophagy, and (2) the mechanism by which C19ORF5 suppresses tumorigenesis through autophagic regulation. The experimental approach will use C19ORF5 knockout mice carrying a transgenic autophagic marker GFP-LC3 and their primary hepatocyte cultures as models for biochemical, cell biological and cancer biological studies. The ultimate goal is to understand the general mechanism of tumor suppression and develop strategies to prevent cancers at their origin and terminate cancer relapse after therapy in general using the hepatoma as a prototype.

Public Health Relevance

It is estimated that about half of ageing-related human diseases are caused by accumulation of cellular garbage due to dysfunction in mechanisms for cleaning up mis-folded/aggregated proteins and worn-out dysfunctional organelles. Autophagy, mitophagy when applied to mitochondria, maintains a healthy population of mitochondria and eliminates the toxic macromolecular waste so that oxidative stress-induced genomic instability is prevented. C19ORF5 regulates autophagy in general and mitophagy in particular and prevents tumorigenesis. The new knowledge will eventually lead to develop strategies to terminate cancer at its earliest origin, sensitize human cancers to radiation treatment and chemotherapy, and prevent tumor re-growth and disease recurrence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA142862-05
Application #
8678701
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Salnikow, Konstantin
Project Start
2010-07-02
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$228,817
Indirect Cost
$72,628
Name
Texas A&M University
Department
Biology
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
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Guo, Zhenghui; Chen, Xianju; Du, Tao et al. (2017) Elevated levels of epithelial cell transforming sequence 2 predicts poor prognosis for prostate cancer. Med Oncol 34:13
Jiang, Min-Yao; Han, Zhao-Dong; Li, Wenjiao et al. (2017) Mitochondrion-associated protein peroxiredoxin 3 promotes benign prostatic hyperplasia through autophagy suppression and pyroptosis activation. Oncotarget :
Huang, Hai; Du, Tao; Zhang, Yiming et al. (2017) Elevation of SHARPIN Protein Levels in Prostate Adenocarcinomas Promotes Metastasis and Impairs Patient Survivals. Prostate 77:718-728
Jiang, Min-Yao; Han, Zhao-Dong; Li, Wenjiao et al. (2017) Mitochondrion-associated protein peroxiredoxin 3 promotes benign prostatic hyperplasia through autophagy suppression and pyroptosis activation. Oncotarget 8:80295-80302
Huang, Hai; Du, Tao; Xu, Guibin et al. (2017) Matrine suppresses invasion of castration-resistant prostate cancer cells by downregulating MMP-2/9 via NF-?B signaling pathway. Int J Oncol 50:640-648
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Shi, Ming; Zhang, Yifan; Liu, Leyuan et al. (2016) MAP1S Protein Regulates the Phagocytosis of Bacteria and Toll-like Receptor (TLR) Signaling. J Biol Chem 291:1243-50
Xu, Guibin; Jiang, Yaodong; Xiao, Yuansong et al. (2016) Fast clearance of lipid droplets through MAP1S-activated autophagy suppresses clear cell renal cell carcinomas and promotes patient survival. Oncotarget 7:6255-65
Xu, Guibin; Yue, Fei; Huang, Hai et al. (2016) Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis. Aging (Albany NY) 8:977-85

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