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c-Myc depletion inhibits proliferation of human tumor cells at various stages of the cell cycle

Abstract

A major role for c-Myc in the proliferation of normal cells is attributed to its ability to promote progression through G1 and into S phase of the cell cycle. The absolute requirement of c-Myc for cell cycle progression in human tumor cells has not been comprehensively addressed. In the present work, we used a lentiviral-based short hairpin RNA (shRNA) expression vector to stably reduce c-Myc expression in a large number of human tumor cell lines and in three different types of normal human cells. In all cases, cell proliferation was severely inhibited, with normal cells ultimately undergoing G0/G1 growth arrest. In contrast, tumor cells demonstrated a much more variable cell cycle response with cells from several lines accumulating in S or G2/M phases. Moreover, in some tumor lines, the phase of cell cycle arrest caused by inhibition of c-Myc could be altered by depleting tumor suppressor protein p53 or its transcriptional target p21CIP/WAF. Our data suggest that, as in the case of normal cells, c-Myc is essential for sustaining proliferation of human tumor cells. However its rate-limiting role in cell cycle control is variable and is reliant upon the status of other cell cycle regulators.

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Acknowledgements

We are grateful to Dr Gary Fisher, Dr Andrzej Dlugosz and Dr Laure Rittie for critical reading of the manuscript. We thank John Lazo, David Hackham and Yatin Vyas for cell lines, Jie Lu for DNA sequencing, Josh Solomon for assistance in the initial optimization of lentiviral infection protocols and MaryBeth Ribblet and Suresh Patil for technical assistance. This work was supported by Dermatology Research Foundation Carrier Development Award to MAN, NIH grants R01-CA120244-A1 to MAN, RO1-CA105033, RO1-CA078259 to EVP and R01-CA107237 to MSS. MAN is a Melanoma Research Foundation Scholar. HW was supported by a postdoctoral fellowship award from the Research Advisory Committee of Children's Hospital of Pittsburgh.

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Correspondence to M A Nikiforov.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Wang, H., Mannava, S., Grachtchouk, V. et al. c-Myc depletion inhibits proliferation of human tumor cells at various stages of the cell cycle. Oncogene 27, 1905–1915 (2008). https://doi.org/10.1038/sj.onc.1210823

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