Journal
ONCOTARGETS AND THERAPY
Volume 11, Issue -, Pages 6647-6656Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/OTT.S180520
Keywords
Pim 1; ovarian cancer; c-Myc; glycolysis; SMI4a; therapeutic target
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Funding
- Science and Technology Commission of Shanghai Municipality [15411962000, 17411963000, KW1514, JGYXLJ1502, 2013ZYJB0201]
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Background: Ovarian cancer (OC) is the leading cause of death among women with gynecologic malignancies. Recent studies have highlighted the role of Pim 1, which belongs to a group of constitutively activated serine/threonine kinases, in cancer development. However, the effect of Pim 1 in OC is largely unclear. Methods: OC cell lines with Pim 1 overexpression or knockdown were constructed with lentivirus transduction. Cell Counting Kit-8, colony formation, glycolysis stress test and in vivo mice models were carried out to assess the effect of Pim 1 on OC biological functions. Co-immunoprecipitation assay coupled with western blot were performed to explore the intrinsic mechanisms of Pim 1 in OC. Bioinformatic analysis was then performed to evaluate the expression and prognostic value of Pim 1. Results: We present the first evidence that silencing or overexpressing Pim 1 can suppress or promote, respectively, OC cell proliferation. Furthermore, we demonstrated that Pim 1 can significantly enhance glycolysis in OC cells. In vivo experiments further confirmed that knockdown of Pim 1 inhibits the growth of tumors derived from the SKOV3 cell line. To search for the underlying molecular mechanism, we examined the effect of Pim1 on MYC, a pivotal gene in glycolysis, and observed that Pim 1-mediated phosphorylation of c-Myc activated the expression of glycolysis-associated key genes such as PGK1 and LDHA. Moreover, we found that the Pim 1 inhibitor SM14a induced chemosensitization to cisplatin. Clinically, Pim 1 was also overexpressed in OC and correlated with poor overall survival by bioinformatics analysis. Conclusion: Together, these results suggest that Pim 1 contributes to proliferation and glycolysis in OC via interaction with MYC and may serve as a potential target in the treatment of OC patients.
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