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Inhibition of cell death by ribosomal protein L35a
Charles D Lopez1, Gary Martinovsky, Louie Naumovski
1Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, MC L586, Portland, OR 97201-3098, USA. lopezc@ohsu.edu
Abstract:
In order to better understand how tumor cells develop resistance to chemotherapy drugs, we screened a human cDNA expression library in Jurkat cells for cDNA's that conferred resistance to doxorubicin-induced cell death. One of the cDNA's isolated in the screen codes for ribosomal protein L35a, a component of the large subunit of the ribosome. Jurkat cells engineered to overexpress L35a protein were more resistant not only to doxorubicin but also to UV-irradiation, anti-Fas antibody, and serum starvation compared to Jurkat cells expressing endogenous levels of L35a. Jurkat cells overexpressing L35a did not have increased levels of the anti-apoptotic proteins Bcl-2 or Bcl-xL, the drug efflux pump P-glycoprotein, nor altered cellular growth kinetics or total protein synthesis. Our results provide new insight into L35a function and suggest that it may have a role in the cellular response to cytotoxic damage. Since L35a RNA is overexpressed in a significant number of glioblastoma multiforme (GBM) brain tumors, our results may stimulate further investigation into the possible role of L35a in the resistance of GBM to cytotoxic therapy.
Insights
Researchers identified ribosomal protein L35a as a key factor in cellular resistance to chemotherapy and cytotoxic damage. Overexpression of L35a enhances cell survival against various stressors, suggesting a novel role in cancer therapy resistance.
Area of Science:
- Molecular Biology
- Cellular Biology
- Cancer Research
Background:
- Tumor cells frequently develop resistance to chemotherapy, limiting treatment efficacy.
- Understanding the molecular mechanisms underlying drug resistance is crucial for developing effective cancer therapies.
Purpose of the Study:
- To identify novel genes conferring resistance to doxorubicin-induced cell death.
- To investigate the function of identified genes in cellular stress response and chemoresistance.
Main Methods:
- Screening of a human cDNA expression library in Jurkat cells for doxorubicin resistance.
- Engineering Jurkat cells to overexpress candidate genes.
- Assessing cellular resistance to doxorubicin, UV-irradiation, anti-Fas antibody, and serum starvation.
- Analyzing levels of anti-apoptotic proteins (Bcl-2, Bcl-xL), P-glycoprotein, and protein synthesis.
Main Results:
- Ribosomal protein L35a (RPL35a) was identified as a gene conferring resistance to doxorubicin.
- Overexpression of RPL35a increased resistance to doxorubicin, UV-irradiation, anti-Fas antibody, and serum starvation.
- RPL35a overexpression did not affect Bcl-2, Bcl-xL, P-glycoprotein levels, or cellular growth and protein synthesis.
Conclusions:
- Ribosomal protein L35a plays a significant role in cellular resistance to various cytotoxic insults.
- RPL35a may be involved in the cellular response to DNA damage and apoptosis.
- Overexpression of RPL35a in glioblastoma multiforme suggests its potential role in brain tumor chemoresistance, warranting further investigation.