Open AccessCancer‐associated fibroblasts contribute to cisplatin resistance by modulating ANXA 3 in lung cancer cells
Author(s) -
Wang Limin,
Li Xueqin,
Ren Yinghui,
Geng Hua,
Zhang Qicheng,
Cao Limin,
Meng Zhaowei,
Wu Xiang,
Xu Meilin,
Xu Ke
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13998
Subject(s) - cisplatin , lung cancer , cancer research , cancer cell , apoptosis , stromal cell , cancer , chemistry , metastasis , annexin , kinase , medicine , pathology , chemotherapy , biochemistry
Cancer tissues consist of cancer cells, surrounding stromal cells and the extracellular matrix. Cancer‐associated fibroblasts ( CAF ) are one of the key components of stromal cells. CAF have a great impact on the behavior of cancer cells, including proliferation, invasion, metastasis and chemoresistance in many ways. However, the underlying mechanism had not been fully elucidated. In this study, we investigated the role of CAF in cisplatin resistance of lung cancer cells. By using conditioned medium from CAF ( CAF ‐ CM ), we found that CAF decreased the sensitivity of lung cancer cells to cisplatin. RNA sequencing results showed that CAF expressed a higher level of Annexin A3 ( ANXA 3) than normal fibroblasts ( NF ), and CAF ‐ CM incubation increased the ANXA 3 level in lung cancer cells. Overexpression of ANXA 3 in lung cancer cells increased cisplatin resistance and activated c‐jun N‐terminal kinase ( JNK ), whereas knockdown of ANXA 3 increased cisplatin sensitivity. Further study showed that CAF ‐ CM enhanced cisplatin resistance by inhibiting cisplatin‐induced apoptosis, determined by repression of caspase‐3 and caspase‐8, through activation of the ANXA 3/ JNK pathway. Conversely, suppression of JNK activation by specific inhibitor retarded the effect of CAF ‐ CM and ANXA 3 on cisplatin sensitivity. Taken together, our study demonstrated that CAF potentiated chemoresistance of lung cancer cells through a novel ANXA 3/ JNK pathway both in vitro and in vivo, suggesting ANXA 3 could be a potential therapeutic target for the treatment of chemoresistant cancer.