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Failure to activate caspase 3 in phorbol ester-resistant leukemia cells is associated with resistance to apoptotic

Yun-Jung Choi1, Jong-Wook Park, Ju-Hyung Woo

  • 1Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, 700-712, Taegu, South Korea.

Cancer Letters
|June 6, 2002
PubMed

Insights

The protein kinase C (PKC) inhibitor Ro-31-8220 triggers apoptosis in leukemia cells via caspase activation and cytochrome c release. Resistance in derivative cells suggests Akt activation may protect against this PKC inhibitor-induced cell death.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Protein kinase C (PKC) inhibitors, such as Ro-31-8220, demonstrate anti-proliferative and apoptotic effects on human cancer cell lines.
  • Understanding the precise molecular mechanisms underlying Ro-31-8220-induced apoptosis is crucial for its therapeutic development.

Purpose of the Study:

  • To elucidate the molecular pathways involved in apoptosis induced by the PKC-specific inhibitor Ro-31-8220.
  • To compare the cellular response to Ro-31-8220 in a human leukemia cell line (U937) and a resistant derivative (R-U937).

Main Methods:

  • Treatment of U937 and R-U937 cells with Ro-31-8220.
  • Assessment of apoptosis through caspase 3 activation, phospholipase C (PLC)-gamma1 cleavage, and cytochrome c release.
  • Evaluation of Bcl-2 family protein and IAP family protein expression.
  • Measurement of Akt activation levels.

Main Results:

  • Ro-31-8220 induced apoptosis in U937 cells, evidenced by caspase 3 activation and cytochrome c release.
  • The caspase inhibitor z-VAD-fmk blocked Ro-31-8220-induced apoptosis, confirming the role of caspases.
  • R-U937 cells, resistant to Ro-31-8220, did not exhibit cytochrome c release or caspase 3 activation.
  • Enhanced Akt activation was observed in R-U937 cells compared to U937 cells, potentially conferring resistance.

Conclusions:

  • Ro-31-8220 induces apoptosis in U937 leukemia cells through a caspase-dependent pathway involving cytochrome c release.
  • Resistance to Ro-31-8220 in R-U937 cells is associated with higher Akt activation and a lack of caspase-mediated apoptosis.
  • Akt activation may play a protective role against Ro-31-8220-induced apoptosis.

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