Abstract
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.
Highlights
Breast cancer is the most common malignant disease in US women and is a leading cause of cancer mortality.[1]
We examined by western blotting the expression of PTBP1 in a series of progressively transformed human mammary epithelial cells (HMECs) as well as in the breast cancer cell lines MCF-7, T47D and MDA-MB231
The level of PTBP1 is considerably higher in malignant transformed HMECs (184AA2 and 184AA3) and breast cancer cells than in HMEC without malignant properties (184A1). These results indicate that PTBP1 is associated with, and may be involved in, the neoplastic transformation of HMEC; its upregulation is likely an early event in the transformation process
Summary
Breast cancer is the most common malignant disease in US women and is a leading cause of cancer mortality.[1]. PTBP1 is an RNA-binding protein with various molecular functions related to RNA metabolism. It is a major repressive regulator of alternative splicing, causing exon skipping in numerous alternatively spliced pre-mRNAs.[9] It is involved in the 30-end processing of mRNA, affecting 30-end cleavage and polyadenylation.[10,11] PTBP1 was found to have a role in the control of mRNA stability: binding of PTBP1 to the 30-untranslated region has been shown to increase the stability of mRNAs such as rat insulin, vascular endothelial growth factor and CD154.12–15
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