B7-H3 Induces Ovarian Cancer Drugs Resistance Through An PI3K/AKT/BCL-2 Signaling Pathway

Li Zhou; Yangchun Zhao

doi:10.2147/CMAR.S222224

B7-H3 Induces Ovarian Cancer Drugs Resistance Through An PI3K/AKT/BCL-2 Signaling Pathway

Cancer Manag Res. 2019 Dec 3:11:10205-10214. doi: 10.2147/CMAR.S222224. eCollection 2019.

Authors

Li Zhou¹, Yangchun Zhao²

Affiliations

¹ Department of Gynecology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
² Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People's Republic of China.

Abstract

Purpose: This study was aimed to investigate the underlying mechanism of B7-H3 induced ovarian cancer proliferation and drugs resistance.

Materials and methods: We compared the expression of B7-H3 in ovarian tumor tissues from high-malignant or low-malignant patients by immunohistochemistry. We established B7-H3 overexpression and knockout ovarian cells by CRISPR-Cas9 technology and examined the expression of the PI3K/AKT/BCL-2 signals in tumor cells by Western blot or immunofluorescence. We detected the B7-H3 overexpression ovarian cancer cells drugs resistance by CCK8 cell proliferation analysis and Annexin V/PI staining. Tumor-bearing mice were used to investigate the anticancer effects of PI3K/AKT inhibitors in combination with B7-H3 neutralizing antibodies.

Results: Enhanced expression of B7-H3 was observed in ovarian tumor tissues from high-malignant patients compared to those from low-malignant patients. Notably, B7-H3 overexpression caused enhanced cells proliferation and chemo-resistance in vitro and in vivo through the activation of PI3K/AKT signaling pathways and up-regulation of BCL-2 protein. Combination of chemotherapeutic agents and B7-H3 neutralizing antibodies efficiently reverses the drugs resistance induced by B7-H3, resulting in improved anticancer effects in ovarian cancer.

Conclusion: B7-H3 expression induces the activation the PI3K/AKT signaling pathway and up-regulates BCL-2 in protein level, resulting in the sustained growth and chemo-resistance in ovarian cancer. Blockade of B7-H3 signals efficiently reverses the chemo-resistance, which provides an innovative target in ovarian cancer treatment.

Keywords: AKT; B7-H3; BCL-2; CD276; PI3K; ovarian cancer.