Dead or dying: Necrosis versus apoptosis in caspase-deficient human renal cell carcinoma

The antitumor effect of immuno- and chemotherapeutic agents is executed thr ough stimulation of apoptotic programs in susceptible cells. Apoptosis indu ced in tumor cells requires activation of members of the caspase family of proteases. Deficient expression or activation of caspases may account in pa rt for the failure of many current anticancer therapies, However, recent st udies suggest that cell death can proceed in the absence of caspases, We in vestigated the susceptibility of human renal cell carcinoma (RCC) lines to two distinct modes of cell death, apoptosis and necrosis, RCC lines display ed 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 cell s. Conversely, TPEN was a potent inducer of apoptosis in caspase-competent normal kidney cells (NK-72) and Jurkat T lymphocytes. Resistance to apoptos is in RCC lines correlated with almost complete loss of caspase-3 expressio n and variable down-regulation of caspase-7, caspase-8, and caspase-10, The se data may explain the resistance of RCC to drugs inducing apoptosis and h ave important consequences for further attempts to manipulate tumor cell de ath.