Abstract
Most tumors frequently undergo initial treatment with a chemotherapeutic agent but ultimately develop resistance, which limits the success of chemotherapies. As cisplatin exerts a high therapeutic effect in a variety of cancer types, it is often used in diverse strategies, such as neoadjuvant, adjuvant and combination chemotherapies. However, cisplatin resistance has often manifested regardless of cancer type, and it represents an unmet clinical need. Since we found that API5 expression was positively correlated with chemotherapy resistance in several specimens from patients with cervical cancer, we decided to investigate whether API5 is involved in the development of resistance after chemotherapy and to explore whether targeting API5 or its downstream effectors can reverse chemo-resistance. For this purpose, cisplatin-resistant cells (CaSki P3 CR) were established using three rounds of in vivo selection with cisplatin in a xenografted mouse. In the CaSki P3 CR cells, we observed that API5 acted as a chemo-resistant factor by rendering cancer cells resistant to cisplatin-induced apoptosis. Mechanistic investigations revealed that API5 mediated chemo-resistance by activating FGFR1 signaling, which led to Bim degradation. Importantly, FGFR1 inhibition using either an siRNA or a specific inhibitor disrupted cisplatin resistance in various types of API5high cancer cells in an in vitro cell culture system as well as in an in vivo xenograft model. Thus, our results demonstrated that API5 promotes chemo-resistance and that targeting either API5 or its downstream FGFR1 effectors can sensitize chemo-refractory cancers.
Highlights
Traditional therapies such as surgery, chemotherapy and radiotherapy are implemented to treat many cancer types
Received December 2016; revised February 2017; accepted 15 March 2017 showed that resistance to cytotoxic T lymphocyte-induced apoptosis in cancer cells after immunotherapies was associated with upregulation of the anti-apoptotic gene API5.19–23 we discovered that API5 mediates immune resistance by upregulating the FGFR1/ERK pathway, which regulates the levels of the pro-apoptotic molecule Bim.[19]
In this report, we demonstrated that acquired resistance after repeated treatments with cisplatin is related to high levels of API5 expression and downregulation of the pro-apoptotic molecule Bim via FGFR/ERK signaling in human cancer cells
Summary
Traditional therapies such as surgery, chemotherapy and radiotherapy are implemented to treat many cancer types. Chemotherapy is frequently used in diverse strategies, including neoadjuvant, adjuvant and combination chemotherapies.[1] Many patients with different types of cancers (for example, cervical, head and neck, non-small cell lung, gastric and bladder cancer) have been preferentially treated with cisplatin chemotherapy.[2,3,4] Cisplatin (cis-diaminedichloroplatinum) is a platinum compound that was discovered in the 1960s and is one of the most potent chemotherapeutic drugs used for cancer treatment.[5,6] Its mechanism involves DNA binding and the subsequent activation of multiple signaling pathways to induce cell cycle arrest and apoptosis. To fulfill this unmet clinical need among cancer patients with cisplatin resistance, studies have tried to provide definitive evidence regarding the mechanisms of the novel drug targets that can be used with cisplatin
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call