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Death of Tumor Cells after Intracellular Acidification Is Dependent on Stress-activated Protein Kinases (SAPK/JNK) Pathway Activation and Cannot Be Inhibited by Bcl-2 Expression or Interleukin 1ß-converting Enzyme Inhibition¹

Departments of Medicine [B. W. Z., I. F. T.] and Medical Biophysics [B. W. Z., C. L., S. A., I. F. T.], The Princess Margaret Hospital and The Ontario Cancer Institute, Toronto, Ontario, M5G 2M9 Canada

The extracellular microenvironment of tumors differs from that of most normal tissues. Many tumors have relatively acidic extracellular pH, although the intracellular pH of tumor cells remains normal due to the efficient maintenance of a large proton gradient across the membrane. This difference between tumors and normal tissues might be exploited therapeutically by disruption of the mechanisms that regulate intracellular pH, so that tumor cells are killed by intracellular acid-induced injury. To investigate the mechanisms by which intracellular acidification leads to cell death, we have studied the roles of the antiapoptotic gene bcl-2 and its proapoptotic binding partner bax, the stress-activated protein kinases (SAPK/JNK), and the caspase proteases in mediating acid-induced cell death. Whereas the expression of bcl-2 in human bladder cancer MGH-U1 cells had no effect on acid-induced death, overexpression of bax enhanced cell death, consistent with its proapoptotic function. Inhibition of SAPK, through the expression of a dominant negative mutant of its activator, SEK1, protected cells from acid-induced cell death. Caspase activation, as measured by poly(ADP-ribose) polymerase cleavage, was absent after lethal intracellular acidification. Consistent with this observation, inhibition of interleukin 1ß-converting enzyme proteases by the peptide z-Val-Ala-Asp(OMe)-CH₂F did not protect against acid-induced cell killing. We conclude that acid-induced cell death depends on bax and on SAPK signaling pathways, but not on the caspase proteases. Therapeutic manipulation of bax and SAPK may enhance acid-induced tumor cell killing.

¹ Supported by grants from the National Cancer Institute of Canada (to B. W. Z. and I. F. T.). B. W. Z. is a recipient of an MRC Clinician-Scientist Award.

² To whom requests for reprints should be addressed, at Department of Medicine, The Princess Margaret Hospital and The Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario, M5G 2M9 Canada. E-mail: zanke@oci.utoronto.ca.

Received 11/26/97. Accepted 5/ 5/98.

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