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Dead or dying: necrosis versus apoptosis in caspase-deficient human renal cell carcinoma
V Kolenko1, R G Uzzo, R Bukowski
1Department of Immunology, The Cleveland Clinic Foundation, Ohio 44195, USA.
Abstract:
The antitumor effect of immuno- and chemotherapeutic agents is executed through stimulation of apoptotic programs in susceptible cells. Apoptosis induced in tumor cells requires activation of members of the caspase family of proteases. Deficient expression or activation of caspases may account in part for the failure of many current anticancer therapies. However, recent studies suggest that cell death can proceed in the absence of caspases. We investigated the susceptibility of human renal cell carcinoma (RCC) lines to two distinct modes of cell death, apoptosis and necrosis. RCC lines displayed almost complete resistance to apoptosis in response to the intracellular zinc chelator, N,N,N'N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), which instead induced dramatic accumulation of nonapoptotic necrotic cells. Conversely, TPEN was a potent inducer of apoptosis in caspase-competent normal kidney cells (NK-72) and Jurkat T lymphocytes. Resistance to apoptosis in RCC lines correlated with almost complete loss of caspase-3 expression and variable down-regulation of caspase-7, caspase-8, and caspase-10. These data may explain the resistance of RCC to drugs inducing apoptosis and have important consequences for further attempts to manipulate tumor cell death.
Insights
Human renal cell carcinoma (RCC) lines resist apoptosis due to deficient caspase expression, leading to necrosis instead. This explains therapeutic resistance and suggests new cancer treatment strategies targeting cell death pathways.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Anticancer therapies rely on apoptosis, a programmed cell death pathway.
- Caspase activation is crucial for apoptosis induction.
- Caspase deficiency in tumors can lead to therapeutic resistance.
Purpose of the Study:
- To investigate the differential susceptibility of human renal cell carcinoma (RCC) lines to apoptosis and necrosis.
- To identify the role of caspases in RCC cell death.
- To understand the mechanisms underlying RCC resistance to apoptosis-inducing agents.
Main Methods:
- Exposure of RCC lines, normal kidney cells (NK-72), and Jurkat T lymphocytes to the intracellular zinc chelator TPEN.
- Assessment of cell death modes (apoptosis vs. necrosis) using TPEN.
- Analysis of caspase-3, -7, -8, and -10 expression levels in RCC lines.
Main Results:
- RCC lines were resistant to TPEN-induced apoptosis, exhibiting necrosis instead.
- TPEN potently induced apoptosis in normal kidney cells and lymphocytes.
- RCC resistance correlated with loss of caspase-3 and reduced expression of other caspases (caspase-7, -8, -10).
Conclusions:
- Deficient caspase expression, particularly caspase-3, underlies apoptosis resistance in RCC.
- This caspase deficiency explains the ineffectiveness of certain anticancer drugs against RCC.
- Targeting alternative cell death pathways or restoring caspase function may overcome therapeutic resistance in RCC.