Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer |
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Authors: | A Zeuner F Francescangeli P Contavalli G Zapparelli T Apuzzo A Eramo M Baiocchi M L De Angelis M Biffoni G Sette M Todaro G Stassi R De Maria |
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Institution: | 1.Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy;2.Department of Surgical and Oncological Sciences, University of Palermo, Palermo 90128, Italy;3.Regina Elena National Cancer Institute, Rome, Italy |
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Abstract: | Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-XL is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-XL inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-XL. In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/slow-proliferating LCSC strongly depend on Bcl-XL for their survival and indicate Bcl-XL inhibition as a potential therapeutic avenue in NSCLC.Lung cancer is the leading cause of cancer-related death in men and is expected to become the main cause of cancer death for women in the near future.1, 2 There is increasing evidence that cancer stem cells (CSCs) have a key role in drug resistance, tumor progression and metastasis in multiple tumor types, including lung cancer.3 Lung cancer stem cells (LCSCs) have been previously identified through different criteria including surface expression of CD133, c-kit or through functional properties such as selective drug survival, elevated aldehyde dehydrogenase (ALDH) activity, increased glycolysis and glycine/serine metabolism or low concentrations of reactive oxygen species and ATP.4, 5, 6, 7, 8, 9 Importantly, when inoculated into immunocompromised mice, LCSCs give rise to xenografts that histologically reproduce the tumor of origin, thus representing an improved model for in vivo testing of new targeted therapies.10 Several tumors express elevated levels of anti-apoptotic Bcl-2 family proteins such as Bcl-2, Bcl-XL and Mcl-1, which affect the apoptotic threshold of neoplastic cells contributing to chemotherapy resistance.11 Inhibition of anti-apoptotic Bcl-2 family members has been for long time regarded as a promising strategy to induce cancer cell death through approaches of increasing specificity. BH3 mimetics such as ABT-737, the related orally available ABT-263 (navitoclax) and the recently developed Bcl-2-selective inhibitor ABT-199 have been shown to exert an antitumor effect in preclinical and clinical settings either as single agents or in combination with conventional or targeted drugs.12 Recently, a new role for Bcl-2 has emerged in acute myeloid leukemia (AML), where quiescent stem cells characterized by low levels of reactive oxygen species were found to overexpress Bcl-2 and rely on this factor for survival.13 Similarly, in chronic myeloid leukemia (CML), quiescent therapy-resistant stem cells were sensitized to tyrosine kinase inhibitors by treatment with a pan-Bcl-2 inhibitor.14 In solid tumors, the role of Bcl-2 family members in regulating the stem cell compartment is less clear. By analyzing the expression and relative function of Bcl-2 and Bcl-XL in LCSC, we identified a prevalent role of Bcl-XL in LCSC survival. Differently from chemotherapy, ABT-737 showed a preferential cytotoxic activity towards quiescent/slowly proliferating LCSC in vitro indicating a potential use of this inhibitor to eradicate chemotherapy-resistant LCSC. In vivo, ABT-737 blocked the progression of LCSC-derived xenografts and reduced CSC content, substantiating its specific effect on the CSC compartment. Altogether, these results indicate for the first time a key role of Bcl-XL in LCSC, opening new perspectives for the elimination of therapy-resistant cells. |
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