Regulation of replicative and stress-induced senescence by RSK4, which is down-regulated in human tumors
Laura López-Vicente1, Gemma Armengol, Berta Pons
1Department of Pathology, Vall d'Hebron University Hospital, and Department of Biochemistry and Molecular Biology, and Unit of Biological Anthropology, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.
Purpose:
The control of senescence and its biochemical pathways is a crucial factor for understanding cell transformation. In a large RNA interference screen, the RSK4 gene was found to be related to p53-dependent arrest. The purpose of the present study was to investigate the potential role of RSK4 as a tumor suppressor gene.
Experimental Design:
RSK4 expression was determined by quantitative real-time PCR and immunoblot in 30 colon and 20 renal carcinomas, and in 7 colon adenomas. Two HCT116 colon carcinoma cell lines (p53 wt and p53 null), IMR90 human fibroblasts, and E1A-expressing IMR90 cells were infected with RSK4 cDNA and/or shRNA. RSK4 expression levels were analyzed in HCT116 p53 wt or p53 null and IMR90 after senescence induction by quantitative real-time PCR and Western blot.
Results:
The RSK4 gene was down-regulated in 27 of 30 colon carcinomas (P < 0.001), 16 of 20 renal cell carcinomas (P < 0.01), and 6 of 7 colon adenomas (P < 0.01). In vitro overexpression of RSK4 induced cell arrest and senescence features in normal fibroblasts and malignant colon carcinoma cell lines. Interestingly, in these cell lines RSK4 mRNA levels were increased both in replicative and stress-induced senescence. Moreover, IMR90 partially immortalized by RSK4 shRNA and HCT116 with this short hairpin RNA were more resistant to cisplatin treatment. Finally, cells expressing E1A or Rb short interfering RNA were resistant to RSK4-mediated senescence.
Conclusion:
These results support the concept that RSK4 may be an important tumor suppressor gene by modulating senescence induction and contributing to cell proliferation control in colon carcinogenesis and renal cell carcinomas.
Insights
The RSK4 gene, often downregulated in colon and renal carcinomas, acts as a tumor suppressor by inducing senescence and controlling cell proliferation. Its restoration may offer therapeutic potential in cancer treatment.
Area of Science:
- Oncology
- Cell Biology
- Molecular Genetics
Background:
- Cellular senescence is critical for understanding and controlling cell transformation.
- RSK4 gene was identified in an RNA interference screen as being related to p53-dependent cell arrest.
- Investigating RSK4's function is key to understanding its role in cancer development.
Purpose of the Study:
- To investigate the potential role of RSK4 as a tumor suppressor gene.
- To determine the impact of RSK4 on cell proliferation and senescence.
- To explore RSK4's involvement in colon and renal carcinogenesis.
Main Methods:
- Quantitative real-time PCR and immunoblotting were used to assess RSK4 expression in tumor samples and cell lines.
- RSK4 cDNA and shRNA were used to manipulate RSK4 expression in colon carcinoma cell lines and human fibroblasts.
- Senescence was induced via replicative stress and analyzed through molecular techniques.
Main Results:
- RSK4 gene was significantly downregulated in colon carcinomas, renal cell carcinomas, and colon adenomas.
- Overexpression of RSK4 induced cell cycle arrest and senescence features in normal and cancer cells.
- RSK4 levels increased during both replicative and stress-induced senescence, and its suppression conferred resistance to cisplatin treatment.
Conclusions:
- RSK4 functions as a tumor suppressor gene by modulating senescence induction.
- RSK4 plays a role in controlling cell proliferation, particularly in colon and renal cancers.
- These findings suggest RSK4 as a potential therapeutic target for cancer treatment.
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