Journal of Molecular Medicine

, Volume 96, Issue 11, pp 1251–1266 | Cite as

The combination of everolimus and terameprocol exerts synergistic antiproliferative effects in endometrial cancer: molecular role of insulin-like growth factor binding protein 2

  • Angel Chao
  • Chiao-Yun Lin
  • Ren-Chin Wu
  • Yun-Shien Lee
  • Li-Yu Lee
  • Chia-Lung Tsai
  • Lan-Yan Yang
  • Hsuan Liu
  • Shu-Jen Chen
  • Tzu-Hao WangEmail author
  • Chyong-Huey LaiEmail author
Original Article


Oncogenic PIK3CA mutations are common in endometrial cancers, and the PI3K/AKT/mTOR pathway is targetable by drugs. We sought to investigate whether the combination of an mTOR inhibitor, everolimus (RAD001), and an AKT inhibitor, terameprocol (M4N), exerts better antiproliferative effects in endometrial cancer. The molecular mechanisms underlying their pharmacological action were also examined. The combination of RAD001 and M4N exerted in vitro synergistic effects on cell viability, apoptosis, and expression of IGFBP2 in endometrial cancer cells. Mechanistically, the Sp1 site on the IGFBP2 promoter was required for RAD001- and M4N-induced downregulation. IGFBP2 protein expression was higher in endometrial cancer than in the normal endometrium (P < 0.001). Furthermore, elevated IGFBP2 histoscores were significantly associated with a lower overall survival (P = 0.021). In conclusion, our in vitro results demonstrate that RAD001 and M4N exert synergistic antiproliferative effects against endometrial cancer cells, which appeared to be mediated by the inhibition of IGFBP2, a key anti-apoptotic regulator. Further clinical studies of this drug combination in patients with endometrial cancer may be warranted, especially in the presence of PIK3CA and IGFBP2 aberrations.

Key messages

  • RAD001 and M4N synergistically suppress endometrial cancer growth.

  • IGFBP2 is overexpressed in endometrial cancer.

  • The combination of RAD001 and M4N significantly reduces IGFBP2 overexpression.

  • Sp1 binding site on the IGFBP2 promoter is required for RAD001- and M4N-induced downregulation.

  • High IGFBP2 histoscore in endometrial cancer portends a poor prognosis.


Everolimus Terameprocol Endometrial cancer Insulin-like growth factor binding protein 2 



We are grateful to Ms. Jung-Erh Yang for her excellent technical assistance. Formalin-fixed paraffin-embedded specimens were kindly provided by the Tumor Bank. We also acknowledge the statistical assistance provided by the Clinical Trial Center (Chang Gung Memorial Hospital, Linkou, Taiwan), which was founded by the Taiwanese Ministry of Health and Welfare (grant MOHW106-TDU-B-212-113005).

Funding information

This study was financially supported by grants from the Chang Gung Foundation (CMRPG3C1351/2/3, CMRPG3G1781, CRRPG3D0041-3, and CMRPG3F2111/2) and the Ministry of Science and Technology (MOST 105-2320-B-182A-005).

Compliance with ethical standards

Conflict of interest

SJC is an employee of ACT Genomics Co., Ltd.

Supplementary material

109_2018_1699_MOESM1_ESM.doc (10 mb)
ESM 1 (DOC 10214 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Angel Chao
    • 1
    • 2
  • Chiao-Yun Lin
    • 2
  • Ren-Chin Wu
    • 3
  • Yun-Shien Lee
    • 4
  • Li-Yu Lee
    • 3
  • Chia-Lung Tsai
    • 5
  • Lan-Yan Yang
    • 6
  • Hsuan Liu
    • 7
  • Shu-Jen Chen
    • 8
  • Tzu-Hao Wang
    • 1
    • 2
    Email author
  • Chyong-Huey Lai
    • 1
    • 2
    Email author
  1. 1.Department of Obstetrics and GynecologyChang Gung Memorial Hospital, Linkou Branch, and Chang Gung University College of MedicineTaoyuanTaiwan
  2. 2.Gynecologic Cancer Research CenterChang Gung Memorial Hospital Linkou Medical CenterTaoyuanTaiwan
  3. 3.Department of Pathology, College of MedicineChang Gung Memorial Hospital Linkou Medical Center and Chang Gung UniversityTaoyuanTaiwan
  4. 4.Department of BiotechnologyMing Chuan UniversityTaoyuanTaiwan
  5. 5.Genomic Medicine Research Core LaboratoryChang Gung Memorial Hospital Linkou Medical CenterTaoyuanTaiwan
  6. 6.Biostatistics Unit, Clinical Trial CenterChang Gung Memorial Hospital Linkou Medical CenterTaipeiTaiwan
  7. 7.Chang Gung Molecular Medicine Research CenterChang Gung UniversityTaoyuanTaiwan
  8. 8.ACT Genomics, Co. Ltd.Taipei CityTaiwan

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