Tumor suppressor candidate 1 (TUSC1) drives oxidative phosphorylation and tumor cell death in colorectal cancer
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Isolation and Characterization of Tumor-initiating Cells from Sarcoma Patient-derived Xenografts
Published on: June 13, 2019
Janvie Manhas1, Ruchi Bhardwaj2, Sagar Tyagi2
1Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India. manhasjanvi11@gmail.com.
Abstract:
Tumor Suppressor Candidate-1 (TUSC1), located at chromosome 9p21.2, resides within a region frequently deleted in human malignancies, yet its role in colorectal cancer (CRC) remains undefined. We investigated TUSC1 expression and function using integrated clinical, transcriptomic, metabolic, and in-vivo approaches. Immunohistochemical analysis of 145 CRC specimens revealed a significant loss of TUSC1 protein compared to normal colon, concordant with TCGA-COAD/READ RNA-Seq datasets. DepMap CRISPR fitness screens demonstrated that TUSC1 is non-essential for baseline proliferation, supporting a tumor suppressor-like profile. Lentiviral re-expression of TUSC1 in low-expressing CRC cell lines (HCT116, SW480) induced broad transcriptomic remodeling, including suppression of PI3K-Akt-mTOR signaling and stemness programs, with concomitant enrichment of oxidative phosphorylation (OXPHOS) pathways. Quantitative proteomics and phospho-western analyses confirmed attenuation of PI3K-Akt signaling. TUSC1 overexpression led to increased mitochondrial respiration, Complex I activity, and mitochondrial mass without significant changes in glycolytic flux. It also led to elevated mitochondrial ROS levels and induced G2/M arrest and apoptosis. Antioxidants partially rescued mitochondrial ROS-dependent cytotoxicity in HCT116 cells, whereas SW480 cells displayed a more limited redox rescue. TUSC1 also reduced cancer stem cell markers, impaired clonogenicity, enhanced 5-fluorouracil sensitivity, and suppressed tumor growth in xenograft models. These findings establish TUSC1 as a metabolic tumor suppressor in CRC that attenuates PI3K-Akt signaling, enhances mitochondrial oxidative metabolism, and promotes ROS-mediated tumor cell death. This study provides the first mechanistic insight into TUSC1's function in cancer, and its restoration or therapeutic induction of oxidative metabolic stress may represent a strategy for targeting CRCs.
Insights
Tumor Suppressor Candidate-1 (TUSC1) acts as a metabolic tumor suppressor in colorectal cancer (CRC). Restoring TUSC1 function may offer a new strategy for CRC treatment by promoting oxidative stress and cell death.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Research
Background:
- Tumor Suppressor Candidate-1 (TUSC1) is located in a frequently deleted chromosomal region (9p21.2) but its role in colorectal cancer (CRC) is unknown.
- TUSC1's tumor suppressor-like profile is supported by its non-essential role in baseline cancer cell proliferation.
Purpose of the Study:
- To investigate the expression and function of TUSC1 in colorectal cancer.
- To elucidate the molecular mechanisms by which TUSC1 influences CRC progression and metabolism.
Main Methods:
- Immunohistochemistry on CRC specimens and TCGA-COAD/READ RNA-Seq analysis for TUSC1 expression.
- CRISPR fitness screens, lentiviral TUSC1 re-expression, transcriptomic and proteomic analyses.
- Assessment of mitochondrial function, reactive oxygen species (ROS) levels, cell cycle, apoptosis, and in-vivo xenograft models.
Main Results:
- TUSC1 protein and RNA are significantly downregulated in CRC compared to normal colon tissue.
- TUSC1 re-expression suppressed PI3K-Akt-mTOR signaling, enhanced oxidative phosphorylation (OXPHOS), increased mitochondrial ROS, and induced G2/M arrest and apoptosis.
- TUSC1 reduced cancer stemness, impaired clonogenicity, increased 5-FU sensitivity, and suppressed tumor growth in vivo.
Conclusions:
- TUSC1 functions as a metabolic tumor suppressor in CRC by modulating PI3K-Akt signaling and promoting mitochondrial oxidative metabolism.
- TUSC1 induces ROS-mediated tumor cell death, suggesting its restoration or therapeutic induction of oxidative stress as a potential CRC treatment strategy.
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