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Targeting MET transcription as a therapeutic strategy in multiple myeloma

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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.

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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

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Acknowledgments

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

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Authors and Affiliations

  1. Department of Experimental Therapeutics, Unit 71, Univ. Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Cornel J. Phillip, Christine M. Stellrecht & Varsha Gandhi

  2. Graduate School of Biomedical Sciences, University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA

    Cornel J. Phillip

  3. Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA

    Varsha Gandhi

  4. Department of Pathobiology, CVMNAH, Tuskegee University, Tuskegee, AL, 36088, USA

    Ramadevi Nimmanapalli

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  1. Cornel J. Phillip
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  2. Christine M. Stellrecht
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  4. Varsha Gandhi
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Correspondence to Varsha Gandhi.

Additional information

Supported by grants CA81534, CA85915, and CA100632 from the National Cancer Institute, Department of Health and Human Services and CA16672, the CCSG Core grant.

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Phillip, C.J., Stellrecht, C.M., Nimmanapalli, R. et al. Targeting MET transcription as a therapeutic strategy in multiple myeloma. Cancer Chemother Pharmacol 63, 587–597 (2009). https://doi.org/10.1007/s00280-008-0770-2

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