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Interdependent regulation of intracellular acidification and SHP-1 in apoptosis

M Thangaraju1, K Sharma, D Liu

  • 1Fraser Laboratories, McGill University and Royal Victoria Hospital, Montreal, Quebec, Canada.

Cancer Research
|April 10, 1999
PubMed

Insights

Somatostatin (SST) triggers breast cancer cell death by acidifying the cell interior, a process dependent on SHP-1. This SHP-1-mediated acidification and apoptosis can be targeted for novel cancer therapies.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • G protein-coupled receptor agonist somatostatin (SST) induces apoptosis in MCF-7 human breast cancer cells.
  • SST-induced apoptosis is linked to wild-type p53, Bax, and acidic endonuclease induction.
  • Cytotoxic signaling of SST is mediated by membrane-associated SHP-1 and requires a decrease in intracellular pH (pHi) to 6.5.

Purpose of the Study:

  • To investigate the relationship between intracellular acidification and SHP-1 in cytotoxic signaling.
  • To determine the role of pHi in SST-induced apoptosis.
  • To explore the potential of targeting SHP-1 and intracellular acidification for cancer therapy.

Main Methods:

  • Clamping pHi using the proton-ionophore nigericin.
  • Investigating apoptosis induction at various pHi levels.
  • Assessing SHP-1 translocation and activity using its inactive mutant (SHP-1C455S).
  • Inhibiting Na+/H+ exchanger and H+ ATPase to induce acidification.
  • Evaluating apoptosis in different breast cancer cell lines (MCF-7, T47D, MDA-MB-231).

Main Results:

  • Clamping pHi at 7.25 abolished SST-induced apoptosis but not SHP-1, p53, or Bax regulation.
  • Nigericin-induced pHi clamping to 6.5 triggered apoptosis, with optimal induction between pHi 6.0 and 6.7.
  • pHi-dependent apoptosis involved SHP-1 translocation to the membrane and was abolished by SHP-1C455S.
  • Acidification via Na+/H+ exchanger and H+ ATPase inhibition mimicked SST's effect on pHi and apoptosis.
  • SHP-1-dependent apoptosis was observed in both SST-sensitive and SST-insensitive breast cancer cell lines.

Conclusions:

  • SST-induced SHP-1-dependent acidification occurs independently of p53 and Bax induction.
  • SST may induce intracellular acidification by inhibiting Na+/H+ exchanger and H+ ATPase.
  • SHP-1 is crucial for both agonist-induced acidification and the execution of acidification-dependent apoptosis.
  • Targeting SHP-1 and intracellular acidification presents a novel therapeutic strategy for cancer, potentially bypassing receptor-mediated signaling.

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