Akt pathway activation reduces platelet apoptosis and contributes to the increase of platelet counts in solid tumor patients

Abstract

Platelets counts increase in various cancer patients, which is associated with poor prognosis. However, the cause of high platelet counts in cancer patients is still not fully understood. Here we demonstrated that compared with healthy controls, there were significant differences in platelet parameters, mean platelet volume (MPV), platelet distribution width (PDW), platelet larger cell ratio (P-LCR), and platelet crit (PCT), reflecting platelet volume in breast cancer patients by clinical retrospective analysis. The mitochondrial transmembrane potential (ΔΨm) depolarization and phosphatidylserine (PS) externalization declined, accompanied by reduced expression of pro-apoptotic factors Bak, Bax and apoptotic executor caspase-3, and elevated of anti-apoptotic factor Bcl-xl in various cancer patients’ platelets. Notably, the phosphorylation level of Akt and its downstream target Bad increased in platelets from cancer patients. MK2206, the inhibitor of Akt, reduced the phosphorylation level of Akt and Bad, and induced apoptosis of platelets. When platelets from healthy controls cocultured with the cultural supernatant of cancer cells, the phosphorylation level of Akt and Bad in the platelets was elevated and the cultural supernatant of cancer cells could rescue the apoptosis of platelet induced by MK2206. Therefore, in our study the apoptosis of platelets in cancer patients was declined, which exerted an influence on the rise of platelet counts in breast cancer patients. The cross-talking between tumor and platelets could affect platelet apoptosis by regulating Akt signaling pathway in platelets.

Keywords:

• Akt signaling pathway
• apoptosis
• cancer
• cross-talking
• platelet

Acknowledgements

We thank the nurses in Sun Yat-Sen Breast Cancer Hospital for their excellent support in blood samples collecting.

Author Contributions

YFY and TH designed the study, and was a major contributor in writing and revising the manuscript. TH, LQ, LHH, ZZX collected samples. TH, HSY, LQ performed experiments, LZC analyzed data. HSY, FWC, ZJH contributed to the discussion and analysis of some of the data. All authors read and approved the final manuscript. YFY supervised the study.

Availability of Data and Materials

The data and materials that support the findings of this study are available upon request to [email protected] with permission of Sun Yat-Sen Memorial Hospital.

Disclosure Statement

No potential conflict of interest was reported by the author(s).

Ethics Approval and Consent to Participate

The study was conducted in accordance with the principles of the Declaration of Helsinki. Approval for obtaining whole-blood samples from healthy volunteers and patients was obtained from the Ethics Committee of the Sun Yat-Sen Memorial Hospital, and all participants gave written informed consent. Informed consent was waived for this retrospective study. No animals were used in the current study.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [81972467] and the Natural Science Foundation of Guangdong Province [2020A1515010458].