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Interaction of androgen receptor and MID1/PP2A/α4 complex and implications on prostate cancer progression and therapy

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  1. Tez No: 401204
  2. Yazar: ÜMMÜHAN DEMİR
  3. Danışmanlar: PROF. HELMUTH KLOCKER
  4. Tez Türü: Doktora
  5. Konular: Tıbbi Biyoloji, Medical Biology
  6. Anahtar Kelimeler: Belirtilmemiş.
  7. Yıl: 2013
  8. Dil: İngilizce
  9. Üniversite: Medızınısche Unıversıtat Innsbruck
  10. Enstitü: Yurtdışı Enstitü
  11. Ana Bilim Dalı: Belirtilmemiş.
  12. Bilim Dalı: Belirtilmemiş.
  13. Sayfa Sayısı: Belirtilmemiş.

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Özet (Çeviri)

The MID1 protein is an ubiquitin ligase. The gene encoding MID1 is mutated in a developmental syndrome called Opitz G/BBB. MID1 forms the core of a ribonuclear protein complex including also PP2A and α4 proteins and several mRNAs carrying MIDAS sequences. Until now the studies on MID1 is mostly limited to the Opitz syndrome. AR is a transcription factor commonly aberrated in advanced prostate cancer. Its mRNA has CAG and GGY repeats in its 5' translated region, through which it is associated with the MID1/PP2A/α4 complex. Based on this data, we hypothesized that the MID1/PP2A/α4 complex plays a role in the progression of prostate cancer In our study, we found that the MID1/PP2A/α4 complex regulates AR in a posttranscriptional way. Interestingly, in a reverse manner, MID1 is an AR target gene and is negatively regulated by androgens. IHC revealed that MID1 expression in prostate tissue samples has a distinct pattern. MID1 is mainly found in the stromal cells in benign parts of the tissue. In cancerous tissue, expression of MID1 shifted to the epithelial cancer part and increased in correlation with the Gleason score of the tumors. Tumor tissue samples exhibiting a distinct histological pattern called cribriform displayed significantly higher MID1 expression. Metformin, an anti-diabetic agent, has anti-tumor effects in many types of cancer. Recently, it was reported that it targets the MID1/PP2A/α4 complex. Therefore, we decided to study the function of the MID1/PP2A/α4 complex in prostate cancer, in particular its effects on androgen receptor. In our study, metformin showed an anti-proliferative effect in prostate cancer cells and decreased AR protein levels. In the same manner, knock-down of MID1 in prostate cancer cell lines decreased proliferation as well as AR protein level. This anti-tumor effect of metformin was independent of AMPK a key target of the anti-diabetic effects of metformin. As the underlying mechanism of metformin inhibition of prostate cancer cells dissociation of AR mRNA from the MID1/PP2A/ α4 complex was identified. Our findings revealed that there is a mutual feedback regulation between AR and MID1. Androgen deprivation therapy can disturb this regulation and result in AR upregulation suggesting a role of MID1 in progression of the disease to a therapy-resistant stage. Metformin targets the MID1/PP2A/α4 complex and with that indirectly the AR. Taken together these findings support the use of metformin for the therapy of CRPC.

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