Journal
ONCOTARGET
Volume 5, Issue 17, Pages 7525-7539Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2265
Keywords
nutrient deprivation; Beclin-1-independent autophagy; HIF-1 alpha; IRES; hypoxia; ATG5-independent autophagy
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Funding
- National Science Council [NSC 100-2320-B-002 -088 -MY3]
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Hypoxia has been shown to induce hypoxia-inducible factor-1alpha (HIF-1 alpha) expression to support many cellular changes required for tumor growth and metastasis. In addition to hypoxia, nutrient deprivation is another stress condition widely existing in solid tumors due to the poor blood supply. Our data showed that nutrient deprivation induces a significant HIF-1 alpha protein expression and potentiates the HIF-1 alpha responses of hypoxia and CoCl2. This effect is not because of enhancement of HIF-1 alpha stability or transcription. Rather we found it is through the cap-independent but internal ribosome entry site (IRES)-dependent translation. Notably inhibition of autophagy by si-ATG5, 3-methyladenine and chloroquine, but not si-Beclin-1, significantly reverses nutrient deprivation-induced HIF-1 alpha responses. Furthermore, it is interesting to note the contribution of IRES activation for hypoxia-induced HIF-1 alpha expression, however, different from nutrient starvation, si-Beclin 1 but not si-ATG5 can inhibit hypoxia-induced HIF-1 alpha IRES activation and protein expression. Taken together, we for the first time highlight a link from alternative autophagy to cap-independent protein translation of HIF-1 alpha under two unique stress conditions. We demonstrate Beclin 1-independent autophagy is involved to positively regulate nutrient deprivation induced-HIF-1 alpha IRES activity and protein expression, while ATG5-independent autophagy is involved in the HIF-1 IRES activation caused by hypoxia.
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