Cancer‐associated fibroblasts contribute to cisplatin resistance by modulating ANXA3 in lung cancer cells

Abstract

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.

Annexin A3 in sepsis: novel perspectives from an exploration of public transcriptome data

“…The findings obtained thus far point towards a potential use of ANXA3 as a diagnostic, prognostic and predictive biomarker for cancer patient management 38–41 . More relevant to the sepsis profiling data presented and discussed here, mechanistic studies point to a role played by ANXA3 in promoting cancer growth and metastasis 42–45 . Notably, a recent study also reported benefits of anti‐ANXA3 monoclonal antibodies in a preclinical mouse model of HCC 45 .…”

“…49 It is notable that, on one hand, improved tumour-cell survival and proliferation was shown to be mediated, in part, by ANXA3-mediated caspase 3 (CASP3) suppression. 45,50,51 And in vascular smooth muscle cells a decrease in CASP3 levels was also shown to accompany inhibition of apoptosis and increased proliferation induced by ANXA3. 52 On the other hand, CASP3 is also well-known to mediate neutrophil programmed cell death: indeed over 1000 records being returned by the PubMed query: neutrophil* AND ('Caspase 3' OR CASP3).…”

New Insights into Mechanisms of Cisplatin Resistance: From Tumor Cell to Microenvironment

“…In addition to CAM-DR, interactions between stromal and tumor cells can also modify the ECM and secret growth factors, support tumor angiogenesis, suppress anticancer immune response, and therefore produce a TME niche that promotes drug resistance. Carcinoma-associated fibroblasts (CAFs) are the predominant cell type within the TME, and their associations with CDDP resistance have been widely explored [73,74,75,76,77,78]. In most studies using CAF coculture methods, tumor cells obtained CDDP resistance through CAF-secreted chemokines or growth factors, such as interleukin (IL)-6, IL-8, IL-11, insulin-like growth factor 1, or transforming growth factor-β (TGF-β).…”

Mitochondria at Center of Exchanges between Cancer Cells and Cancer-Associated Fibroblasts during Tumor Progression

“…Instead, CAFs epigenetically downregulate caspase expression, inducing transcription factor STAT1, thus limiting caspases 9, 3 and 7 activation. In in vitro and in vivo lung cancer models, CAFs secretion of Annexin A3 has been shown to stimulate cancer cells survivin, known to inhibit caspases activity, thus leading to the decrease in caspases 3 and 8 cleavage under cisplatin treatment [ 44 ]. Similarly, CAFs protect lung and ovarian cancer cells from cisplatin via increasing survivin by promoting STAT3 phosphorylation [ 32 , 33 ].…”