Abstract
Up-regulation of anti-apoptotic factors is a critical mechanism of cancer cell resistance and often counteracts the success of chemotherapeutic treatment. Herein, we identified the cancer-associated RNA-binding protein La as novel factor contributing to cisplatin resistance. Our data demonstrate that depletion of the RNA-binding protein La in head and neck squamous cell carcinoma cells (HNSCC) increases the sensitivity toward cisplatin-induced cell death paralleled by reduced expression of the anti-apoptotic factor Bcl2. Furthermore, it is shown that transient expression of Bcl2 in La-depleted cells protects against cisplatin-induced cell death. By dissecting the underlying mechanism we report herein, that the La protein is required for Bcl2 protein synthesis in cisplatin-treated cells. The RNA chaperone La binds in close proximity to the authentic translation start site and unwinds a secondary structure embedding the authentic AUG. Altogether, our data support a novel model, whereby cancer-associated La protein contributes to cisplatin resistance by stimulating the translation of anti-apoptotic factor Bcl2 in HNSCC cells.
Highlights
The human La protein (LARP3, La/SSB) is an RNA-binding protein that is overexpressed in various types of cancer [1,2,3], and stimulates proliferation, migration, and invasion of cancer cells in vitro [2,3,4] as well as tumor growth in vivo [5]
For the first time we present data that the over expression of RNA-binding protein La protects against cisplatin-induced cell death and that depletion of the La www.impactjournals.com/oncotarget protein sensitizes head and neck squamous cell carcinoma (HNSCC) cells to cisplatin
These findings are significant because the La protein is overexpressed in various types of cancer and this study suggests that high La levels contribute to cancer pathogenesis and chemotherapy resistance by counteracting therapeutic treatments aiming to induce cell death
Summary
The human La protein (LARP3, La/SSB) is an RNA-binding protein that is overexpressed in various types of cancer [1,2,3], and stimulates proliferation, migration, and invasion of cancer cells in vitro [2,3,4] as well as tumor growth in vivo [5]. The La protein stimulates translation of mRNAs that have structural RNA elements located within the 5’-untranslated region (5’UTR) in common, like stem-loop structures as described in Mdm2 [1], a negative regulator of tumor suppressor p53, or internal ribosomal entry sites (IRES) as described for various viral and cellular mRNAs including tumor-promoting factors such as X-linked inhibitor of apoptosis (XIAP), cyclin D1, and Laminin B1 [2, 4, 5, 10,11,12,13,14,15,16,17,18]. In recent years ongoing efforts have been made to identify novel inhibitors targeting Bcl expression in cancer cells to improve the outcome of anticancer therapy [31, 32]
Sign-in/Register to view highlights & summary 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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
