The preservation of normal mitochondrial functions is quintessential to the malignant transformation of a cell. The major genes that play a crucial role in this transformation process include oncogenes and tumor suppressor genes; these genes code for the synthesis of proteins that are involved in tumor cell homeostasis. FoxO3A is a tumor suppressor that can either facilitate or hinder the transformation of non-malignant cells. Its functions are mediated by the activation of a coordinated transcriptional program, which involves genes that regulate the control of cell cycle, cell metabolism, cell death, autophagy, redox balance, and DNA repair. The activation of the FoxO3A-dependent transcriptional program in metabolically stressed cancer cells trigger cell cycle arrest and autophagy, which may result in cell death under persistent stress conditions. FoxO3A can promote survival via detoxiﬁcation and DNA repair or reflect an irreparable level of damage via apoptosis. Although recent studies have indicated that the mitochondrial arm of the AMPK-FoxO3A axis functions as a recovery mechanism to sustain cellular metabolism during metabolic stress or nutrient shortage, there is a paucity of information on the characterization and functions of FoxO3A in cancer cells subjected to metabolic stress and chemotherapy.
In a recent international collaboration, Valentina Celestini and colleagues demonstrated novel functions of FoxO3A in cancer cells subjected to metabolic stress and chemotherapy. The research work is published in the journal Cell Death and Disease.
The research team detected a shorter form of FoxO3A in the mitochondria of metabolically stressed HeLa cancer cells. They also found that FoxO3A N-terminus (amino acids 1–148) is required for the localization and translocation of FoxO3A into the mitochondria while residues 98–108 are required for the cleavage and import of FoxO3A into the mitochondrial matrix.
Furthermore, they observed that phosphorylation at S12 and S30 of FoxO3A N-terminus is required for mitochondrial accumulation in metabolically stressed cancer cells and that expression of the mitochondrial genome in metabolically stressed cancer cells is regulated by mitochondrial FoxO3A (mtFoxO3A), while only the AMPK signal is required for the accumulation of FoxO3A into the mitochondria of normal cells under nutrient shortage.
Moreover, the presence of FoxO3A into the mitochondria was found to result in resistance and survival of tumor cells subjected to metabolic stress or chemotherapy. The membrane potential of functionally active and healthy mitochondria of metabolically stressed cancer cells was also found to be maintained by mtFoxO3A, and the induction of metabolic stress on tumor tissues result in FoxO3A mitochondrial localization and the activation of MEK/ERK and AMPK pathways. In addition, they discovered that chemotherapy induces the activation of the MEK/ERK/phoshoS30-mtFoxO3A pathway, which results in chemoresistance of cancer cells. Finally, they showed that metformin could induce apoptosis in cancer cells via the AMPK/phosphoS30-mtFoxO3A axis.
The study was led by Cristiano Simone at the Italian Institute of Gastroenterology “S. de Bellis” and provided compelling evidence that FoxO3A mitochondrial localization via MEK/ERK- and AMPK pathways in metabolically stressed cancer cells promote cell survival, while only MEK/ERK activation is required for mtFoxO3A-dependent chemoresistance. Moreover, the Authors showed that metformin could induce apoptosis via the AMPK/mtFoxO3A axis, and that metformin could revert chemoresistance via mtFoxO3A in cancer cells. These findings are expected to advance further investigations on the development of personalized therapeutic strategies to thwart malignant transformation.
Cristiano Simone is a Professor at the Biomedical Sciences and Human Oncology Department, University of Bari (Italy), where he earned his PhD. Supported by a postdoctoral fellowship from the “Sbarro Health Research Organization”, Prof. Simone completed his post-doctoral training at the Thomas Jefferson University in 2001 and then was appointed as an Associate Researcher at the Clayton Foundation Laboratories for Peptide Biology (The Salk Institute for Biological Studies, California) in 2002, supported by a Telethon grant. In 2008, Cristiano established his research lab at the Consorzio Mario Negri Sud. Then, in 2012, he moved his laboratory to the I.R.C.S.S. Saverio De Bellis of Castellana Grotte (Bari, Italy), where he works as chief of the Medical Genetics Department.
Cristiano Simone’s group research focuses on different cancer-related signaling pathways in colorectal cancer, ovarian cancer and prostate cancer, with the aim of evaluating their manipulation for cancer therapy. One of his main research areas involves p38 signaling and the role of the AMPK/FoxO3A axis in cancer development, autophagy and chemoresistance in colorectal cancer patients, with a view to assess the therapeutic potential of its targeted manipulation in clinical settings. In the FoxO3A field, Prof. Simone’s group disclosed the existence of an inverse correlation between the copy number of the protective G-allele at FoxO3A intronic single nucleotide polymorphism rs2802292 and cancer risk.
Further to this finding, they recently published an article on a prestigious peer-reviewed international journal showing that the 90-bp sequence around rs2802292 has enhancer functions and that the rs2802292 G-allele creates a novel HSE binding site for HSF1, which induces FOXO3 expression in response to diverse stress stimuli. Moreover, Cristiano’s group was among the first to provide evidence of the existence of an intra-mitochondrial form of FoxO3A and then described in detail the AMPK- and MEK/ERK-dependent mechanism of mitochondrial accumulation. Recently, they found another piece of the puzzle by dissecting the nuclear and mitochondrial role of FoxO3A and revealing the involvement of the latter in chemoresistance.
Last but not least, Prof. Simone’s Lab has conducted pioneering research on SMYD3, a histone lysine methyltransferase involved in colorectal cancer cell proliferation. Importantly, his research group showed for the first time the effectiveness of the SMYD3 inhibitor BCI-121 on cell growth in colorectal, lung, pancreatic, prostate and ovarian cancer. Prof. Simone has been working in these areas for more than a decade now and published over 50 peer-reviewed articles and book chapters.
Celestini, V., Tezil, T., Russo, L., Fasano, C., Sanese, P., Forte, G., Peserico, A., Signorile, M.L., Longo, G., De Rasmo, D., Signorile, A., Gadaleta, R.M., Scialpi, N., Terao, M., Garattini, E., Cocco, T., Villani, G., Moschetta, A., Grossi, V., and Simone, C. Uncoupling FoxO3A Mitochondrial and Nuclear Functions in Cancer Cells Undergoing Metabolic Stress and Chemotherapy, Cell Death and Disease 9 (2018) 231