HG 9 91 01 br our study we did not
our study, we did not observe cytotoxic effects of apatinib on ovarian cancer cells. The inhibitory mechanism of apatinib in ovarian cancer cells was further investigated by detecting changes in the cell cycle and cell apoptosis. But, in our study, apatinib did not alter the ovarian cancer cell cycle or cell apoptosis.
In this study, apatinib substantially inhibited the migration and invasion of ovarian cancer cells. (1) Tumour cell motility is an essen-tial factor for tumour invasion and metastasis, and the JAK-STAT3 signalling pathway is commonly over-activated in many physiologi-cal cellular pathways involving cell motility . Accordingly, the JAK-STAT3 signalling pathway plays an important role in cell adhe-sion, migration and other processes. (2) Tumour angiogenesis refers to the growth of HG 9 91 01 induced by tumour cells and the estab-lishment of blood circulation in tumours. According to previous studies [20,21], STAT3 directly regulates the transcription of VEGF, and the persistent overactivation of the JAK-STAT3 signalling path-way in tumour cells therefore promotes tumour angiogenesis through VEGF, thereby resulting in tumour invasion and metastasis.
(3) Degradation of the extracellular matrix (ECM) is a crucial step in tumour invasion and metastasis. The JAK-STAT3 signalling pathway has consistently been shown to be involved in ECM degradation by directly or indirectly regulating the expression of matrix metallopro-teinase genes . (4) During the embryonic development of zebrafish, blockade of the K-Ras signalling pathway impairs haematopoiesis and angiogenesis, suggesting that the PI3K/Akt pathway is involved in haematopoiesis and angiogenesis mediated by the K-Ras signalling pathway . Apatinib inhibits the EMT in ovarian cancer cells by inhibiting the JAK/STAT3 and PI3K/Akt signal-ling pathways to subsequently inhibit ovarian cancer cell motility and invasion, suppress tumour cell volume growth in vivo and indi-rectly inhibit tumour invasion and metastasis by inhibiting tumour angiogenesis.
In summary, apatinib significantly inhibits the biological functions of ovarian cancer cells in vitro and in vivo, and our study provided evi-dence supporting the use of apatinib as a treatment for ovarian cancer in clinical practice.
We are grateful to Mrs. Xiao-yan Cheng for her excellent assistance with these experiments.
All the authors have no conflict of interest.
J Ding: Protocol development, data collection, data analysis and manuscript writing.
X-y Cheng: Data collection, data analysis and manuscript writing.
S Liu: Analysis of tissue responses in the animal model.
H-y Ji: Data collection.
M Lin: Manuscript writing.
R Ma: Protocol development.
F-l Meng: Protocol development.
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aPKCι promotes gallbladder cancer tumorigenesis and gemcitabine T
resistance by competing with Nrf2 for binding to Keap1
Li Tiana, Yun Lua, Tao Yanga, Zhengdong Denga, Lei Xua, Wei Yaob, Chaoqun Maa, Xiangyu Lia, Jian Zhanga, Yan Liuc, Jianming Wanga,∗
a Department of Biliary and Pancreatic Surgery, Aﬃliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
b Department of Oncology, Aﬃliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
c Department of Geriatrics, Aﬃliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
Gallbladder cancer Atypical protein kinase Cι
Reactive oxygen species
Gallbladder cancer (GBC) is a highly malignant bile duct cancer with poor prognosis characterized by its in-sensitivity to chemotherapy. Emerging evidence indicates that cytoprotective antioxidation is involved in drug resistance of various cancers; however, the underlying molecular mechanisms remain obscure. Here, we de-monstrated that atypical protein kinase Cι (aPKCι) mediated reactive oxygen species (ROS) inhibition in a ki-nase-independent manner, which played a crucial role in tumorigenesis and chemoresistance. Mechanistically, we found that aPKCι facilitated nuclear factor erythroid 2-related factor 2 (Nrf2) accumulation, nuclear trans-location and activated its target genes by competing with Nrf2 for binding to Kelch-like ECH-associated protein 1 (Keap1) through a highly conserved DLL motif. In addition, the aPKCι-Keap1 interaction was required for an-tioxidant eﬀect, cell growth and gemcitabine resistance in GBC. Importantly, we further confirmed that aPKCι was frequently upregulated and correlated with poor prognosis in patients with GBC. Collectively, our findings suggested that aPKCι positively modulated the Keap1-Nrf2 pathway to enhance GBC growth and gemcitabine resistance, implying that the aPKCι-Keap1-Nrf2 axis may be a potential approach to overcome the drug re-sistance for the treatment of GBC.