Proproliferative function of adaptor protein GRB10 in prostate carcinoma

Abstract

Growth factor receptor‐binding protein 10 (GRB10) is a well‐known adaptor protein and a recently identified substrate of the mammalian target of rapamycin (mTOR). Depletion of GRB10 increases insulin sensitivity and overexpression suppresses PI3K/Akt signaling. Because the major reason for the limited efficacy of PI3K/Akt‐targeted therapies in prostate cancer (PCa) is loss of mTOR‐regulated feedback suppression, it is therefore important to assess the functional importance and regulation of GRB10 under these conditions. On the basis of these background observations, we explored the status and functional impact of GRB10 in PCa and found maximum expression in phosphatase and tensin homolog (PTEN)‐deficient PCa. In human PCa samples, GRB10 inversely correlated with PTEN and positively correlated with pAKT levels. Knockdown of GRB10 in nontumorigenic PTEN null mouse embryonic fibroblasts and tumorigenic PCa cell lines reduced Akt phosphorylation and selectively activated a panel of receptor tyrosine kinases. Similarly, overexpression of GRB10 in PTEN wild‐type PCa cell lines accelerated tumorigenesis and induced Akt phosphorylation. In PTEN wild‐type PCa, GRB10 overexpression promoted mediated PTEN interaction and degradation. PI3K (but not mTOR) inhibitors reduced GRB10 expression, suggesting primarily PI3K‐driven regulation of GRB10. In summary, our results suggest that GRB10 acts as a major downstream effector of PI3K and has tumor‐promoting effects in prostate cancer.—Khan, M. I., Al Johani, A., Hamid, A., Ateeq, B., Manzar, N., Adhami, V. M., Lall, R. K., Rath, S., Sechi, M., Siddiqui, I. A., Choudhry, H., Zamzami, M. A., Havighurst, T. C., Huang, W., Ntambi, J. M., Mukhtar, H. Proproliferatve function of adaptor protein GRB10 in prostate carcinoma. FASEB J. 33, 3198–3211 (2019). http://www.fasebj.org

GRB10 sustains AR activity by interacting with PP2A in prostate cancer cells

“…GRB10 knockdown in AR‐positive LNCaP and C4‐2 PCa cells inhibited cell proliferation, while its overexpression promoted ENZ resistance. Our findings were later independently confirmed in vivo by another research group 9 . However, the precise mechanism mediated by GRB10 in CRPC development remains unclear.…”

“…GRB10 is reportedly a substrate of mTORC1, where mTORC1 phosphorylates and stabilizes GRB10 in TSC2 ‐deficient models 39 . On the other hand, in PCa models, treatment with either mTOR inhibitors (rapamycin, Torin‐1 and PP242) or amino acid deprivation failed to reduce GRB10 protein expression 9 . In our previous study, we found that the expression of GRB10 mRNA is significantly higher in PTEN ‐deleted clinical PCa 8 .…”

“…39 On the other hand, in PCa models, treatment with either mTOR inhibitors (rapamycin, Torin-1 and PP242) or amino acid deprivation failed to reduce GRB10 protein expression. 9 In our previous study, we found F I G U R E 4 GRB10 inhibits PP2A activity in prostate cancer (PCa) cells. A, The effects of GRB10 knockdown on PP2A phosphatase activity was determined using the PP2A IP phosphatase assay.…”

“…Our findings were later independently confirmed in vivo by another research group. 9 However, the precise mechanism mediated by GRB10 in CRPC development remains unclear.…”

miR-222 Suppresses Immature Porcine Sertoli Cell Growth by Targeting the GRB10 Gene Through Inactivating the PI3K/AKT Signaling Pathway

“…Hundreds of the target genes of miR-222 were predicted using the TargetScan online software, and the GRB10 aroused our attention as it is involved in the regulation of gene transcription and translation, the cell cycle, and cell growth and proliferation by inducing the PI3K-AKT signaling pathway ( Kazi and Ronnstrand, 2013 ; Khan et al, 2019 ; Zhang T. et al, 2019 ). Furthermore, it has been reported that LY294002-induced inhibition of the PI3K/AKT signaling pathway inhibits porcine Sertoli cell proliferation and promotes cell apoptosis ( Gao et al, 2019 ).…”