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bcl-2 plays a major role in resistance to dexamethasone induced apoptosis in multiple myeloma cell lines

W Hu1, Y Gazitt

  • 1UNIV TEXAS,HLTH SCI CTR,DEPT MED,DIV HEMATOL,SAN ANTONIO,TX 78284.

International Journal of Oncology
|May 5, 2011
PubMed

Insights

High bcl-2 protein levels correlate with dexamethasone resistance in multiple myeloma (MM) cells. Down-regulation of bcl-2 and P53 proteins occurs during apoptosis induction in sensitive MM cells.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • The anti-apoptotic protein bcl-2 is a known factor in drug resistance in various cancers, including lymphomas and leukemias.
  • The specific role of bcl-2 in multiple myeloma (MM) apoptosis, especially concerning drug resistance, remains less understood due to the low frequency of the t(14:18) translocation in MM.

Purpose of the Study:

  • To investigate the correlation between steady-state levels of bcl-2, P53, and bar proteins and sensitivity to dexamethasone (DEX)-induced apoptosis in multiple myeloma cell lines.
  • To examine the dynamic changes in these protein levels during DEX-induced apoptosis in both sensitive and resistant MM cells.

Main Methods:

  • Analysis of steady-state protein levels of bcl-2, P53, and bar in four multiple myeloma cell lines using Western blotting or similar techniques.
  • Correlation of protein expression levels with sensitivity to dexamethasone-induced apoptosis, assessed by cell viability assays or apoptosis markers.
  • Monitoring of protein level changes in response to dexamethasone treatment over a 72-hour period in both DEX-sensitive and DEX-resistant cell lines.

Main Results:

  • Multiple myeloma cell lines expressing high bcl-2 protein levels (HS-Sultan, ARH-77) exhibited significant resistance to DEX-induced apoptosis.
  • Cell lines with low bcl-2 protein levels (8226, ARP-1) were considerably more sensitive to DEX, showing 2-3 logs greater sensitivity.
  • In DEX-sensitive cells, apoptosis induction led to early down-regulation of bcl-2 and P53 proteins, while bar protein levels decreased slightly. In contrast, DEX-resistant cells showed no significant changes in bcl-2, bar, or P53 protein levels during DEX treatment.

Conclusions:

  • Steady-state levels of bcl-2 protein are a significant determinant of dexamethasone sensitivity in multiple myeloma cell lines.
  • The observed protein level changes during apoptosis induction align with previously reported mRNA transcript level alterations for these oncogenes.
  • These findings highlight the critical role of bcl-2 in mediating dexamethasone resistance in multiple myeloma.

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