Asymmetric cancer cell division regulated by AKT

Abstract

Human tumors often contain slowly proliferating cancer cells that resist treatment, but we do not know precisely how these cells arise. We show that rapidly proliferating cancer cells can divide asymmetrically to produce slowly proliferating "G0-like" progeny that are enriched following chemotherapy in breast cancer patients. Asymmetric cancer cell division results from asymmetric suppression of AKT/PKB kinase signaling in one daughter cell during telophase of mitosis. Moreover, inhibition of AKT signaling with smallmolecule drugs can induce asymmetric cancer cell division and the production of slow proliferators. Cancer cells therefore appear to continuously flux between symmetric and asymmetric division depending on the precise state of their AKT signaling network. This model may have significant implications for understanding how tumors grow, evade treatment, and recur.quiescence | epigenetics | cell signaling | drug resistance T umors generally evolve through years of mutation and clonal selection (1). This favors the outgrowth of rapidly proliferating cancer cells over time. However, even advanced tumors contain many cancer cells that appear to be proliferating slowly (2). This proliferative heterogeneity correlates closely with time to clinical detection, growth, metastasis, and treatment response across all tumor types, but we still do not understand clearly how it arises. The rate of mammalian cell proliferation is generally determined by the time spent in G1 of the cell cycle. Critical genetic and epigenetic changes within cancer cells accelerate G1 transit, whereas a suboptimal microenvironment with imbalance of growth factors, nutrients, or oxygen can slow G1 progression (3). Therefore, individual cancer cells within a tumor are thought to vary significantly in their proliferative rate depending on the precise balance of these intrinsic and extrinsic factors. Interestingly, however, many tumor-derived cancer cell lines also produce slowly proliferating cells. These established lines have many acquired mutations that drive cell proliferation. They have also been grown ex vivo for years in a stable microenvironment to promote unbridled proliferation. These factors ought to favor a strong purifying selection against slow proliferators. We worked to understand how slowly proliferating cells seem to arise paradoxically in cancer cell lines.Results G0-Like Cancer Cells in Vitro. We began by studying MCF7, a highly proliferative, aneuploid, ER + /HER2 − human breast cancer cell line. This line displays significant proliferative heterogeneity despite mutations in CDKN2A and PIK3CA that cooperatively drive cell-cycle progression (4). We first hypothesized that slowly proliferating MCF7 cells might produce low levels of reactive oxygen species (ROS). This hypothesis was based on previous observations that slowly cycling hematopoietic, neural, and breast adult stem cells and cancer stem cells produce low levels of ROS (5-7). We stained MCF7 cells with 5-(and-6)chloromethyl 1-2′,7′-dichlorohydrofluorescein diacet...

Distinct Subpopulations of Head and Neck Cancer Cells with Different Levels of Intracellular Reactive Oxygen Species Exhibit Diverse Stemness, Proliferation, and Chemosensitivity

“…CICs in colon, breast, and ovaries have been shown to demonstrate the ability to maintain a quiescent state to evade therapy (46)(47)(48). In addition, Dey-Guha and colleagues (49) report that rapidly proliferating cancer cells can produce "G 0 -like" progeny through asymmetric division, which are enriched following chemotherapy in breast cancer. These G 0 phase cells show lower intracellular ROS level and exhibit suppressing AKT expression.…”

Notch1 Receptor Regulates AKT Protein Activation Loop (Thr308) Dephosphorylation through Modulation of the PP2A Phosphatase in Phosphatase and Tensin Homolog (PTEN)-null T-cell Acute Lymphoblastic Leukemia Cells

“…This suggested a causal role for HES1 in the indirect regulation of AKT by Notch1. Further, HES1 contributes to establishment and maintenance of a quiescent phenotype (52), characterized by elevated HES1 and decreased AKT phosphorylation (53). Again, this suggests that HES1 is involved in AKT regulation.…”

WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors

“…27 Recent articles have demonstrated that even established cancer cell lines are not homogeneous, and identified rare, slowly cycling subpopulations in lung, melanoma, breast, and colon cancer cell lines. 22,[28][29][30] During our manuscript preparation, subpopulations of HCC827 cells with a quiescence-like state that resist EGFR TKIs have been reported to be highly susceptible to ABT-737, the predecessor of ABT-263. 29 Moreover, a report showed that HDAC inhibitors synergistically enhanced the levels of EGFR TKI-induced apoptosis in EGFR-mutant lung adenocarcinoma cell lines.…”