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Cancer Chemotherapy and Pharmacology

, Volume 63, Issue 4, pp 587–597 | Cite as

Targeting MET transcription as a therapeutic strategy in multiple myeloma

  • Cornel J. Phillip
  • Christine M. Stellrecht
  • Ramadevi Nimmanapalli
  • Varsha GandhiEmail author
Original Article

Abstract

Multiple myeloma (MM) is an incurable indolent malignancy with an average lifespan of 3 years, underscoring the need for new therapies. Studies have shown that the receptor MET and its ligand hepatocyte growth factor play an important role in proliferation, migration, adhesion, and survival of MM cells. Hence, an effective way to decrease MET receptor may act as a viable therapeutic option. Since MET mRNA and protein have short half-lives, we hypothesized that transcription inhibitor will reduce MET transcript and protein levels and this will lead to cell death. Pharmacological (flavopiridol) and molecular (shRNA) transcription inhibitor were used to impede formation of MET transcripts. The diminution of global RNA synthesis with flavopiridol was related to phosphorylation status of Ser residues (r 2 = 0.90 and 0.92 for Ser2 and Ser5) on the C-terminal-domain of RNA polymerase II. This was accompanied with a time-dependent decrease in MET transcript, which reached to less than 30% (1 μM) and 10% (3 μM) by 24 h. This decline in transcript level was directly associated with a reduction in MET protein level (r 2 = 0.82) and resulted in cell death. Assessment of MET in MM survival was done by using shRNA targeted towards MET. When cells were infected with shRNA viral construct, there was increased cell death with a decline in MET transcript and protein. Taken together, our study demonstrates that MET plays a critical role in the survival and removal or lowering of MET by flavopiridol or shRNA results in the demise of MM cells.

Keywords

Apoptosis Cell survival Flavopiridol MET Multiple myeloma Transcription 

Abbreviations

CTD

C-terminal domain

CLL

Chronic lymphocytic leukemia

CDK

Cyclin-dependent kinase

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

HGF

Hepatocyte growth factor

MM

Multiple myeloma

PARP

Poly (ADP-ribose) polymerase

RNA Pol II

RNA polymerase II

Notes

Acknowledgments

The authors are thankful to Frank Marini, PhD for allowing virus work to be done in his lab facility.

Supplementary material

280_2008_770_MOESM1_ESM.pdf (2.2 mb)
Supplementary Figure (PDF 2278 kb)

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Cornel J. Phillip
    • 1
    • 2
  • Christine M. Stellrecht
    • 1
  • Ramadevi Nimmanapalli
    • 4
  • Varsha Gandhi
    • 1
    • 3
    Email author
  1. 1.Department of Experimental Therapeutics, Unit 71Univ. Texas M. D. Anderson Cancer CenterHoustonUSA
  2. 2.Graduate School of Biomedical SciencesUniversity of Texas M. D. Anderson Cancer CenterHoustonUSA
  3. 3.Department of LeukemiaUniversity of Texas M. D. Anderson Cancer CenterHoustonUSA
  4. 4.Department of Pathobiology, CVMNAHTuskegee UniversityTuskegeeUSA

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