PRKAR1A is a functional tumor suppressor inhibiting ERK/Snail/E-cadherin pathway in lung adenocarcinoma
Shaoqiang Wang1, Yuanda Cheng1, Yingying Zheng2
1Department of Thoracic Surgery, Xiangya Hospital, Central South University, Xiangya Road 87th, Changsha, 410008, Hunan, P. R. China.
Abstract:
Protein Kinase cAMP-Dependent Regulatory Type I Alpha (PRKAR1A) is a tissue-specific extinguisher that transduces a signal through phosphorylation of different target proteins. Loss of PRKAR1A was frequently observed in endocrine neoplasia and stromal cell tumors. However, a few cases were seen in epithelial tumors. Previously, we first found that PRKAR1A was downregulated in lung adenocarcinoma patients. Thus, the present study aimed to clarify its clinical implication and biological function as a tumor suppressor in lung adenocarcinoma. The low levels of PRKAR1A transcript were correlated with tumor progression and poor overall survival. The re-expression of PRKAR1A in H1299 cells suppressed the tumor cell proliferation and migration; stable knockdown (KD) of PRKAR1A in A549 cells enhanced this function both in vitro and in vivo. Moreover, KD of PRKAR1A in A549 cells promoted the statistical colonization of circulating tumor cells to the lungs in nude mice. These effects by PRKAR1A were attributed to inhibiting E-cadherin expression. Elevated E-cadherin significantly suppressed the PRKAR1A-KD induced cell proliferation and migration. Most notably, deletion of PRKAR1A inhibited E-cadherin by activating ERK/Snail signaling. In conclusion, PRKAR1A was a potent suppressor, and through the inhibition of PRKAR1A-ERK-Snail-E-cadherin axis could serve as a potential therapeutic target.
Insights
Protein Kinase cAMP-Dependent Regulatory Type I Alpha (PRKAR1A) acts as a tumor suppressor in lung adenocarcinoma. Downregulation of PRKAR1A promotes tumor progression and metastasis by activating the ERK/Snail/E-cadherin pathway.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Protein Kinase cAMP-Dependent Regulatory Type I Alpha (PRKAR1A) is implicated in various tumors.
- PRKAR1A downregulation was previously observed in lung adenocarcinoma.
- Its precise role as a tumor suppressor in this context requires further elucidation.
Purpose of the Study:
- To investigate the clinical significance of PRKAR1A in lung adenocarcinoma.
- To determine the biological function of PRKAR1A as a tumor suppressor.
- To elucidate the molecular mechanisms underlying PRKAR1A's function.
Main Methods:
- Correlation analysis of PRKAR1A transcript levels with clinical data.
- In vitro studies using cell lines (H1299, A549) with PRKAR1A re-expression or knockdown.
- In vivo metastasis models in nude mice.
- Western blot analysis to assess protein expression and signaling pathways (ERK/Snail/E-cadherin).
Main Results:
- Low PRKAR1A transcript levels correlate with tumor progression and reduced overall survival.
- PRKAR1A re-expression suppressed proliferation and migration; PRKAR1A knockdown enhanced these processes in vitro and in vivo.
- PRKAR1A knockdown promoted lung colonization of circulating tumor cells.
- PRKAR1A inhibits E-cadherin expression by activating the ERK/Snail signaling pathway.
Conclusions:
- PRKAR1A functions as a potent tumor suppressor in lung adenocarcinoma.
- The PRKAR1A-ERK-Snail-E-cadherin axis represents a potential therapeutic target.
- Targeting this pathway may offer new strategies for lung adenocarcinoma treatment.
Related Concept Videos
Abnormal Proliferation
The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
Inhibition of Cdk Activity
PI3K/mTOR/AKT Signaling Pathway
The Ras Gene
Ras is a...


