Suppression of Sirt1 sensitizes lung cancer cells to WEE1 inhibitor MK-1775-induced DNA damage and apoptosis

Abstract

Lung cancer treatment remains a challenge for clinical practice and new therapeutic approaches are urgently needed. Loss of functional WEE1 kinase causes DNA replication stress, DNA damage and unscheduled mitotic entry due to elevated CDK activity. The selective WEE1 inhibitor MK-1775 synergize with DNA-damaging agent to inhibit cancer cell growth. Here we report that inhibition of Sirt1 deacetylase through small interfering RNA or selective inhibitor Ex527 greatly enhances MK-1775-induced growth inhibition and apoptosis in human lung cancer cells. We further demonstrate that Sirt1 interacts and deacetylates homologous recombination (HR) repair machinery proteins, including NBS1 and Rad51. Inhibition of Sirt1 impairs HR repair activity, which causes unrepairable damage when combining MK-1775 and Ex527. Meanwhile, combination of MK-1775 and Ex527 induces cooperative antitumor activity in lung cancer xenograft model in vivo. Thus, our study provides a novel therapeutic strategy to optimize MK-1775 treatment efficiency in lung cancers.

Retracted Article: Aclarubicin regulates glioma cell growth and DNA damage through the SIRT1/PI3K/AKT signaling pathway

“…Hence, we believe that ACR is involved in DNA damage in glioma cells. SIRT1 has been shown to play a role in a variety of cancers, including prostate cancer, hepatocellular carcinoma, 15 lung cancer, 23 and glioma. 13 However, it plays different roles in different cancers, and may act as a tumor promoter or tumor suppressor.…”

“…Previous evidences suggest that SIRT1 and PI3K/AKT pathways are important regulators of DNA damage response and cell apoptosis. [23][24][25] Hence, we next examined the molecular mechanisms underlying the role of ACR in glioma cell growth, apoptosis, and DNA damage. Results showed that, compared to control treatment, ACR treatment markedly increased the protein expression of SIRT1 in U87 and U251 cells ( Fig.…”

Inhibition of WEE1 Suppresses the Tumor Growth in Laryngeal Squamous Cell Carcinoma

“…MK-1775 has been reported that sensitizes cancers of head and neck ( Osman et al, 2015 ), brain ( Matheson et al, 2016b ), and non-small cell lung cancer ( Richer et al, 2017 ) to the DNA-damage drug cisplatin as well as pancreatic cancer cells ( Kausar et al, 2015 ) to gemcitabine. Additionally, MK-1775 has promising synergistic antitumor effect when combined with CHK1 inhibitors LY2603618 and Sirt1 inhibitor Ex527 in various malignancies ( Chen et al, 2017 ; Hauge et al, 2017 ), suggesting a novel strategy for MK-1775-mediated cancer treatment.…”

HOXC13 promotes proliferation of esophageal squamous cell carcinoma via repressing transcription of CASP3

“…Apoptosis is a process of programmed cell death that occurs in multicellular organisms and inhibition of apoptosis can result in a number of cancers . Apoptosis is generally characterized by phosphatidylserine externalization, depolarization of mitochondrial membrane, caspase‐3 activation and DNA fragmentation .…”