PTEN inhibitor VO‑OHpic suppresses TSC2‑/‑ MEFs proliferation by excessively inhibiting autophagy via the PTEN/PRAS40 pathway

Wang,Wenda; Wang,Xu; Guo,Hao; Cai,Yi; Zhang,Yushi; Li,Hanzhong

doi:10.3892/etm.2020.8629

PTEN inhibitor VO‑OHpic suppresses TSC2‑/‑ MEFs proliferation by excessively inhibiting autophagy via the PTEN/PRAS40 pathway

Authors:
- Wenda Wang
- Xu Wang
- Hao Guo
- Yi Cai
- Yushi Zhang
- Hanzhong Li
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Affiliations: Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China, Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
Published online on: March 31, 2020 https://doi.org/10.3892/etm.2020.8629
Pages: 3565-3570
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Tuberous sclerosis complex (TSC) is a relatively rare autosomal dominant disease which involves multiple organs, including the brain, kidney, lung, skin and heart. Renal angiomyolipomas (RAML) are the main causes of mortality in patients with TSC. The preferred treatment for RAML is the use of mTOR inhibitors, but the efficacy of these are not satisfactory. Therefore, an alternative treatment is urgently required. Autophagy levels decline in TSC associated cortical tubers, and the inhibition of autophagy in animal or cell models of TSC may suppress tumor development and cell proliferation. PTEN is a protein tyrosine phosphatase and can inhibit the activation of Akt. In the present study, it was indicated that the PTEN inhibitor, hydroxyl(oxo)vanadium 3‑hydroxypiridine‑2‑carboxylic acid (VO‑OHpic), suppressed proliferation and growth of TSC2‑/‑ murine embryonic fibroblasts (MEFs) by further inhibiting autophagy of cells. The expression levels of human microtubule‑associated protein 1 light chain 3‑I (LC3‑I) and LC3‑II, which are autophagy associated proteins, were demonstrated to decline following VO‑OHpic treatment. The expression levels of phosphorylated proline‑rich Akt substrate 40 kDa (PRAS40) also decreased in TSC2‑/‑ MEFs treated with VO‑OHpic. The PTEN inhibitor may inhibit the proliferation of TSC2‑/‑ MEFs through the PTEN‑PRAS40 pathway by excessively inhibiting autophagy, without the dependence of the Ras homolog, mTORC1 binding/mTOR pathway. PTEN may be a potential therapeutic target for the treatment of TSC. Further in vivo studies are required to confirm these results.

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