Involvement of polypyrimidine.pdf (1.21 MB)

Involvement of polypyrimidine tract-binding protein (PTBP1) in maintaining breast cancer cell growth and malignant properties.

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journal contribution
posted on 04.03.2016 by X. He, A.D. Arslan, T-T. Ho, C. Yuan, M.R. Stampfer, W.T. Beck
We have investigated some roles of splicing factor polypyrimidine tract-binding protein (PTBP1) in human breast cancer. We found that PTBP1 was upregulated in progressively transformed human mammary epithelial cells (HMECs), as well as in breast tumor cell lines compared with HMECs with finite growth potential and found that the level of PTBP1 correlated with the transformation state of HMECs. Knockdown of PTBP1 expression substantially inhibited tumor cell growth, colony formation in soft agar and in vitro invasiveness of breast cancer cell lines, a result similar to what we have reported in ovarian cancer. However, ectopic expression of PTBP1 (as a PTBP1-EGFP fusion protein) did not enhance the proliferation of immortalized HMEC. Rather, PTBP1 expression promoted anchorage-independent growth of an immortalized HMEC as assessed by increased colony formation in soft agar. In addition, we found that knockdown of PTBP1 expression led to upregulation of the expression of the M1 isoform of pyruvate kinase (PKM1) and increase of the ratio of PKM1 vs PKM2. PKM1 has been reported to promote oxidative phosphorylation and reduce tumorigenesis. Correspondingly, we observed increased oxygen consumption in PTBP1-knockdown breast cancer cells. Together, these results suggest that PTBP1 is associated with breast tumorigenesis and appears to be required for tumor cell growth and maintenance of transformed properties. PTBP1 exerts these effects, in part, by regulating the splicing of pyruvate kinase, and consequently alters glucose metabolism and contributes to the Warburg effect.

Funding

This work was supported in part by National Cancer Institute grants RO1 CA40570 and RO1 CA138762 to WTB and in part by the State of Illinois Department of Public Health’s Penny Severns Breast, Cervical and Ovarian Cancer Research Fund to XH. It was conducted in a facility constructed with support from the NCRR NIH Grant C06RR15482. MRS was supported by Department of Defense Grant BCRP BC060444 carried out at Lawrence Berkeley National Laboratory under Contract Number DEAC02-05CH1123.

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Publisher Statement

This is the copy of an article published in Oncogenesis © 2014 Nature Publishing Group. Oncogenesis. 2014. 3. DOI: 10.1038/oncsis.2013.47. © The Author(s).

Publisher

Nature Publishing Group

issn

2157-9024

Issue date

13/01/2014

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