title: PTEN enhances G2/M arrest in etoposide-treated MCF‑7 cells through activation of the ATM pathway.
abstract: As an effective tumor suppressor, phosphatase and tensin homolog (PTEN) has attracted the increased attention of scientists. Recent studies have shown that PTEN plays unique roles in the DNA damage response (DDR) and can interact with the Chk1 pathway. However, little is known about how PTEN contributes to DDR through the ATM-Chk2 pathway. It is well-known that etoposide induces G2/M arrest in a variety of cell lines, including MCF-7 cells. The DNA damage-induced G2/M arrest results from the activation of protein kinase ataxia telangiectasia mutated (ATM), followed by the activation of Chk2 that subsequently inactivates CDC25C, resulting in G2/M arrest. In the present study, we assessed the contribution of PTEN to the etoposide-induced G2/M cell cycle arrest. PTEN was knocked down in MCF-7 cells by specific shRNA, and the effects of PTEN on the ATM-Chk2 pathway were investigated through various approaches. The results showed that knockdown of PTEN strongly antagonized ATM activation in response to etoposide treatment, and thereby reduced the phosphorylation level of ATM substrates, including H2AX, P53 and Chk2. Furthermore, depletion of PTEN reduced the etoposide-induced phosphorylation of CDC25C and strikingly compromised etoposide-induced G2/M arrest in the MCF-7 cells. Altogether, we demonstrated that PTEN plays a unique role in etoposide-induced G2/M arrest by facilitating the activation of the ATM pathway, and PTEN was required for the proper activation of checkpoints in response to DNA damage in MCF-7 cells.
authors.affiliation: Department of Obstetrics and Gynecology, Shenzhen Maternity and Child Healthcare Hospital, Affiliated to Southern Medical University, Longgang, Shenzhen, Guangdong 518028, P.R. China.
authors.forename: Ruopeng
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Reproductive Medicine, Affiliated Hospital of Dali University, Dali, Yunnan 671000, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Reproductive Medicine, Affiliated Hospital of Dali University, Dali, Yunnan 671000, P.R. China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Reproductive Medicine, Affiliated Hospital of Dali University, Dali, Yunnan 671000, P.R. China.
authors.forename: Anli
authors.initials: A
authors.lastname: Xu
authors.affiliation: Clinical Medicine College of Dali University, Dali, Yunnan 671000, P.R. China.
authors.forename: Zhengwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Clinical Medicine College of Dali University, Dali, Yunnan 671000, P.R. China.
authors.forename: Yijuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Clinical Medicine College of Dali University, Dali, Yunnan 671000, P.R. China.
authors.forename: Pei
authors.initials: P
authors.lastname: He
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Maoqing
authors.initials: M
authors.lastname: Wu
authors.affiliation: The Genetics Laboratory, Shenzhen Longgang District Maternity and Child Healthcare Hospital, Longgang, Shenzhen, Guangdong 518028, P.R. China.
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Wei
authors.affiliation: Department of Obstetrics and Gynecology, Shenzhen Maternity and Child Healthcare Hospital, Affiliated to Southern Medical University, Longgang, Shenzhen, Guangdong 518028, P.R. China.
authors.forename: Chenhong
authors.initials: C
authors.lastname: Wang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C468783:H2AX protein, human; D006657:Histones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human