ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7 (Cell Death and Differentiation 2014, 21:1275-1289)

報告日期: 2015/04/28
報告時間: 15:10/16:00
報告學生: Goutham DVN
講評老師: 張雋曦
附件下載: 下載[1467-1425857794-1.pdf] 

ARHI (DIRAS3) induces autophagy in ovarian cancer

cells by downregulating the epidermal growth factor

receptor, inhibiting PI3K and Ras/MAP signaling and

activating the FOXo3a-mediated induction of Rab7

RC Bast Jr et al. Cell Death and Differentiation (2014) 21, 1275–1289

Speaker:           D.V.N.Goutham                                         Time : 3:10 ~ 4:00, Apr 28,2015

Commentator: Dr. Antonio Cheung                                       Venue: Room 602

Diagnosed worldwide, ovarian cancer is the seventh most common cancer causing death in women. However, the scrupulous mechanisms involved may vary according to their risk factors: hormone therapy, fertility medication and obesity. Increasing evidences have shown that autophagy is one of the prime regulators of cancer cells to defend against variable number of conditions. The role of autophagy in human cancer cells still remains ambiguous and the mechanisms that regulate its outcome are poorly understood.  Earlier research has shown that Aplasia Ras homolg member I (DIRAS3), a maternally imprinted tumor suppressor gene is known to be down-regulated in more than 60% of ovarian and breast cancer cells [1]. Re-expression of ARHI in ovarian cancer cells slows the proliferation, motility and induces autophagy [2]. In this study, authors showed that ARHI induces autophagy by reducing the activity of PI3k/Akt and Ras/ERK that is attained by internalization and further degradation of EGFR. Furthermore, they found that down-regulation of PI3k/Akt and Ras/ERK by ARHI results in decresing the phosphorylation of FOXo3a which sequestrating it back in nucleus to be active. Hence, curbing of FOXo3a in nucleus further stimulates the autophagy maturating genes ATG4 and MAP-LC31 and also increases the expression of Rab7 which is required for autophagosome and lysosomal fusion. In addition, authors also found that ARHI expression is positively correlated with the expression of LC3 and nuclear localization of FOXo3a in ovarian cancer cells of surgical patients. Taken together, these findings suggest that ARHI induces the autophagy to play a suppressing role in ovarian cancer cells.  

REFERENCES:

1.  Lu, Z., et al., DIRAS3 regulates the autophagosome initiation complex in dormant ovarian cancer cells. Autophagy, 2014. 10(6): p. 1071-92.

2. Lu, Z., et al., The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J Clin Invest, 2008. 118(12): p. 3917-29.