OSU-03012 Disrupts Akt Signaling and Prevents Endometrial Carcinoma Progression in vitro and in vivo

Abstract

Purpose

OSU-03012 is a celecoxib derivative lacking cyclooxygenase-2 inhibitory activity and a potent PDK1 inhibitor which has been shown to inhibit tumor growth in various ways. However, the role of OSU-03012 in endometrial carcinoma (EC) in which the PI3K/Akt signaling pathway highly activated has not been studied. Here, we determined the potency of OSU-03012 in suppressing EC progression in vitro and in vivo, and studied the underlined mechanisms.

Methods

The human EC Ishikawa and HEC-1A cells were used as the in vitro models. CCK8 assay and flow cytometry were conducted to evaluate cell proliferation, cell cycle progression, and apoptosis. The metastatic ability was evaluated using the transwell migration assay. The Ishikawa xenograft tumor model was used to study the inhibitory effects of OSU-03012 on EC growth in vivo. Western blot analysis was performed to evaluate expressions of the cell cycle and apoptosis associated proteins.

Results

OSU-03012 could inhibit the progression of EC both in vitro and in vivo by disrupting Akt signaling. It reduced the metastatic ability of EC, led to G2/M cell cycle arrest and induced apoptosis via the mitochondrial apoptosis pathway.

Conclusion

Our data indicated that OSU-03012 could inhibit the progression of EC in vitro and in vivo. It can potentially be used as the targeted drug for the treatment of EC by inhibiting Akt signaling.

Keywords:

• OSU-03012
• endometrial carcinoma
• Akt signaling
• the mitochondrial apoptosis pathway

Acknowledgments

This research was funded by the Key Project of Science and Technology of Henan, grant number 144/22170001.We thank the research group of Professor Ya Xie from the First Affiliated Hospital of Zhengzhou University for great support in Ishikawa cell line. Thanks for the support and guidance provided by Henan Key Laboratory of Digestive Organ Transplantation.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that there are no conflicts of interests in this work.