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KDM1A inhibition augments the efficacy of rapamycin for the treatment of endometrial cancer.
Venkata, Prabhakar Pitta; Chen, Yihong; Alejo, Salvador; He, Yi; Palacios, Bridgitte E; Loeffel, Ilanna; Liu, Junhao; Pratap, Uday P; Gray, Gabrielle; Achuthan Pillai, Sureshkumar Mulampurath; Zou, Yi; Lai, Zhao; Suzuki, Takayoshi; Viswanadhapalli, Suryavathi; Palakurthi, Srinath; Tekmal, Rajeshwar R; Vadlamudi, Ratna K; Kost, Edward; Sareddy, Gangadhara R.
Afiliação
  • Venkata PP; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • Chen Y; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China.
  • Alejo S; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • He Y; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China.
  • Palacios BE; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • Loeffel I; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • Liu J; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China.
  • Pratap UP; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • Gray G; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • Achuthan Pillai SM; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • Zou Y; Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • Lai Z; Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX, 78229, USA; Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • Suzuki T; The Institute of Scientific and Industrial Research, Osaka University, Japan.
  • Viswanadhapalli S; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • Palakurthi S; Department of Pharmaceutical Sciences, Texas A&M University, Kingsville, TX, 78363, USA.
  • Tekmal RR; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA; Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • Vadlamudi RK; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA; Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA; Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
  • Kost E; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • Sareddy GR; Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA; Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA. Electronic address: sareddy@uthscsa.edu.
Cancer Lett ; 524: 219-231, 2022 01 01.
Article em En | MEDLINE | ID: mdl-34673129
Endometrial cancer (EC) often exhibit aberrant activation of PI3K/Akt/mTOR signaling and targeted therapies using mTOR inhibitors showed limited success. The epigenetic modifier, lysine-specific histone demethylase-1A (KDM1A/LSD1) is overexpressed in EC, however, the mechanistic and therapeutic implications of KDM1A in EC are poorly understood. Here, using 119 FDA-approved drugs screen, we identified that KDM1A inhibition is highly synergistic with mTOR inhibitors. Combination therapy of KDM1A and mTOR inhibitors potently reduced the cell viability, survival, and migration of EC cells. Mechanistic studies demonstrated that KDM1A inhibition attenuated the activation of mTOR signaling cascade and abolished rapamycin induced feedback activation of Akt. RNA-seq analysis identified that KDM1A inhibition downregulated the expression of genes involved in rapamycin induced activation of Akt, including the mTORC2 complex. Chromatin immunoprecipitation experiments confirmed KDM1A recruitment to the promoter regions of mTORC2 complex genes and that KDM1A inhibition promoted enrichment of repressive H3K9me2 marks at their promoters. Combination therapy of KDM1A inhibitor and rapamycin reduced the tumor growth in EC xenograft and patient derived xenograft models in vivo and patient derived tumor explants ex vivo. Importantly, in silico analysis of TCGA EC patients data sets revealed that KDM1A expression positively correlated with the levels of PI3K/Akt/mTOR genes. Collectively, our results provide compelling evidence that KDM1A inhibition potentiates the activity of mTOR inhibitors by attenuating the feedback activation of Akt survival signaling. Furthermore, the use of concurrent KDM1A and mTOR inhibitors may be an attractive targeted therapy for EC patients.
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Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Assunto principal: Neoplasias do Endométrio / Histona Desmetilases / Serina-Treonina Quinases TOR / Inibidores de MTOR Limite: Animals / Female / Humans / Male Idioma: En Revista: Cancer Lett Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Assunto principal: Neoplasias do Endométrio / Histona Desmetilases / Serina-Treonina Quinases TOR / Inibidores de MTOR Limite: Animals / Female / Humans / Male Idioma: En Revista: Cancer Lett Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos