| Hypoxia is a physiological condition defined as the oxygen concentration is lower than 5% in general while normoxia is around 20%. It has been reported that hypoxia is related to numerous human diseases, such as respiratory diseases, vascular diseases, neurodegeneration and cancer, and hypoxic stress activates various signal transduction pathways to regulate cellular adaptive responses. Desferroxamine (DFO), a hypoxia-mimetic agent, functions as an iron chelator and has been utilized in hypoxic study. However, the molecular mechanisms underlying hypoxia- and/or DFO-induced adaptive responses are still unclear. In this report, I demonstrate that hypoxia and DFO induce a transient global SUMOylation to augment cell survival against acute hypoxic stress by strengthening passive barrier properties, facilitating the reassembly of F-actin/ZO-1, attenuating pro-apoptotic PKCd/Caspase-3 activation, inducing S1981 phosphorylation of ATM, and activating pro-survival NF-kappaB signaling pathways. Under prolonged hypoxic treatment, DFO induces nuclear translocation and proteolytic cleavage of PKCdelta and PKCdelta-dependent Caspase-3 activation to render a sustained DFO-elicited gamma-H2AX activation leading to apoptotic cell death. Intriguingly, PKCdelta plays a fine-tuning role in modulating DFO-induced Akt phosphorylation. Moreover, DFO-exposure also induces a PKCdelta-independent signaling and both PKCdelta-dependent and -independent pathways functionally cooperate to integrate pro-apoptotic/Caspase-3, pro-survival/Akt, and DNA damage-induced DNA repair/cell cycle regulation signalings. An accumulation of autophagosomes was observed during 2 to 4 h post-hypoxic treatment. Autophagy is a tightly orchestrated intracellular process and is essential for cell survival or death in response to stress conditions. DFO-treatment renders a rapid and transient phosphorylation at Y-64 and Y-155 of PKCdelta and conveys JNK1 Thr183/Tyr185-phosphorylation. Inhibition of PKCdelta by PKCdeltaKD or PKCdelta-knockout reduces DFO-induced changes in LC3-II levels. The requirement of PKCdelta is apparent for DFO-, but not starvation-, induced autophagy. Both JNK1 activation and release of Beclin-1, a key molecule in autophagic process, from inhibitory bcl-2 are PKCdelta-dependent. Significantly, inhibition of autophagy by 3-MA or Atg5-knockout presents a more prevalence in cell death while PKCdelta- or JNK1-deficient cells exhibit resistance to long-term DFO-treatment. In summary, acute hypoxia/DFO stress induces a transient activation of SUMOylation and autophagy to protect cells against hypoxic injury, while prolonged treatment induces PKCdelta proteolytic activation leading to apoptotic cell death. |
