1. Academic Validation
  2. WP1066, a small molecule inhibitor of STAT3, chemosensitizes paclitaxel-resistant ovarian cancer cells to paclitaxel by simultaneously inhibiting the activity of STAT3 and the interaction of STAT3 with Stathmin

WP1066, a small molecule inhibitor of STAT3, chemosensitizes paclitaxel-resistant ovarian cancer cells to paclitaxel by simultaneously inhibiting the activity of STAT3 and the interaction of STAT3 with Stathmin

  • Biochem Pharmacol. 2024 Feb 3:221:116040. doi: 10.1016/j.bcp.2024.116040.
Jun Yang 1 Nanjing Li 2 Xinyu Zhao 1 Wenhao Guo 3 Yang Wu 1 Chunlai Nie 1 Zhu Yuan 4
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Department of Abdominal Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, Sichuan Province, China.
  • 4 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yuanzhu@scu.edu.cn.
Abstract

Paclitaxel is widely used to treat Cancer, however, drug resistance limits its clinical utility. STAT3 is constitutively activated in some cancers, and contributes to chemotherapy resistance. Currently, several STAT3 inhibitors including WP1066 are used in Cancer clinical trials. However, whether WP1066 reverses paclitaxel resistance and the mechanismremains unknown. Here, we report that in contrast to paclitaxel-sensitive parental cells, the expressions of several pro-survival BCL2 family members such as Bcl-2, Bcl-xL and Mcl-1 are higher in paclitaxel-resistant ovarian Cancer cells. Meanwhile, STAT3 is constitutively activated while stathmin loses its activity in paclitaxel-resistant cells. Importantly, WP1066 amplifies the inhibition of cell proliferation, colony-forming ability and Apoptosis of ovarian Cancer cells induced by paclitaxel. Mechanistically, WP1066, on the one hand, interferes the STAT3/Stathmin interaction, causing unleash of STAT3/Stathmin from microtubule, thus destroying microtubule stability. This process results in reduction of Ac-α-tubulin, further causing Mcl-1 reduction. On the other hand, WP1066 inhibits phosphorylation of STAT3 by JAK2, and blocks its nuclear translocation, therefore repressing the transcription of pro-survival targets such as Bcl-2, Bcl-xL and Mcl-1. Finally, the two pathways jointly promote cell death. Our findings reveal a new mechanism wherein WP1066 reverses paclitaxel-resistance of ovarian Cancer cells by dually inhibiting STAT3 activity and STAT3/Stathmin interaction, which may layfoundation for WP1066 combined with paclitaxel in treating paclitaxel-resistant ovarian Cancer.

Keywords

Ovarian cancer; Paclitaxel resistance; STAT3; Stathmin.

Figures
Products