Abstract
Simple SummaryThe PI3K/AKT pathway is involved in cell survival and proliferation. Molecular aberrations and/or hyperactivation of the PI3K-PTEN-AKT axis are frequent in distinct cancer types such as endometrial carcinoma, the most common type of cancer of the female genital tract, and chronic lymphocytic leukemia (CLL), a mature B-cell neoplasm depending on B-cell receptor (BCR) activity, which induces chronical activation of this pathway. The mitochondrial nuclease ENDOG was found to influence PI3K/AKT activity in somatic cells. Our aim was to assess the value of ENDOG gene silencing to block cancer cell proliferation and to evaluate the relevance of ENDOG as prognostic marker. In vivo, in vitro and in silico experiments show that Endog/ENDOG silencing blunts proliferation of tumor cells dependent on high p-AKT/low PTEN activity and that ENDOG has prognostic value in specific cancer types.EndoG influences mitochondrial DNA replication and is involved in somatic cell proliferation. Here, we investigated the effect of ENDOG/Endog expression on proliferation in different tumor models. Noteworthy, ENDOG deficiency reduced proliferation of endometrial tumor cells expressing low PTEN/high p-AKT levels, and Endog deletion blunted the growth of PTEN-deficient 3D endometrial cultures. Furthermore, ENDOG silencing reduced proliferation of follicular thyroid carcinoma and glioblastoma cell lines with high p-AKT expression. High ENDOG expression was associated with a short time to treatment in a cohort of patients with chronic lymphocytic leukemia (CLL), a B-cell lymphoid neoplasm with activation of PI3K/AKT. This clinical impact was observed in the less aggressive CLL subtype with mutated IGHV in which high ENDOG and low PTEN levels were associated with worse outcome. In summary, our results show that reducing ENDOG expression hinders growth of some tumors characterized by low PTEN activity and high p-AKT expression and that ENDOG has prognostic value for some cancer types.
Highlights
Cancer is the second leading cause of death globally, accounting for more than 9 million deaths each year, and its burden continues to growth (WHO https://www.who.int/health-topics/cancer#tab=tab_1, accessed on 18 May 2021)
The results presented here show that reducing ENDOG expression in human tumor cell lines with low Phosphatase and Tensin Homologue (PTEN) expression and high p-AKT abundance restrains cell proliferation
In silico data suggest that ENDOG expression associates with PTEN status in endometrial cancer and that its prognostic value in some chronic lymphocytic leukemia (CLL) subtypes is dependent on PTEN expression levels
Summary
Cancer is the second leading cause of death globally, accounting for more than 9 million deaths each year, and its burden continues to growth (WHO https://www.who.int/health-topics/cancer#tab=tab_1, accessed on 18 May 2021). Lack of ENDOG increases mitochondrial ROS production and slows down cell proliferation in an ROS-dependent manner associated with reduction in the AKT/PKB-GSK-3-Cyclin D axis [8]. This finding adds further evidence on the important role of mitochondrial biology and mitochondria-derived molecules in the control of cytoplasmic transduction signaling that regulates many biological processes [9,10], including cell proliferation [11]. PTEN is one of the most frequently altered tumor suppressor genes in human cancer [15] by different mechanisms including mutation with loss of heterozygosity (LOH), promoter methylation or other processes that lead to its decreased expression [16]
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