| Abstract: |
DIRAS3 is an imprinted tumor suppressor gene that is downregulated in 60% of human ovarian cancers. Re-expression of DIRAS 3 at physiological levels inhibits proliferation, decreases motility, induces autophagy, and regulates tumor dormancy. Functional inhibition of autophagy with choroquine in dormant xenografts that express DIRAS 3 significantly delays tumor regrowth after DIRAS 3 levels are reduced, suggesting that autophagy sustains dormant ovarian cancer cells. This study documents a newly discovered role for DIRAS 3 in forming the autophagosome initiation complex (AIC) that contains BEC N1, PIK3C3, PIK3R4, ATG14, and DIRAS 3. Participation of BEC N1 in the AIC is inhibited by binding of BEC N1 homodimers to BCL2. DIRAS 3 binds BEC N1, disrupting BEC N1 homodimers and displacing BCL2. Binding of DIRAS 3 to BEC N1 increases the association of BEC N1 with PIK3C3 and ATG14, facilitating AIC activation. Amino acid starvation of cells induces DIRAS 3 expression, reduces BEC N1-BCL2 interaction and promotes autophagy, whereas DIRAS 3 depletion blocks amino acid starvation-induced autophagy. In primary ovarian cancers, punctate expression of DIRAS 3, BEC N1, and the autophagic biomarker MAP1LC3 are highly correlated (P < 0.0001), underlining the clinical relevance of these mechanistic studies. Punctate expression of DIRAS 3 and MAP1LC3 was detected in only 21-23% of primary ovarian cancers but in 81-84% of tumor nodules found on the peritoneal surface at second-look operations following primary chemotherapy. This reflects a 4-fold increase (P < 0.0001) in autophagy between primary disease and post-treatment recurrence. We suggest that DIRAS 3 not only regulates the AIC, but induces autophagy in dormant, nutrient-deprived ovarian cancer cells that remain after conventional chemotherapy, facilitating their survival. © 2014 Landes Bioscience. |
