Nuclear receptor coactivator RAC3 inhibits autophagy

Abstract

RAC3 is an oncogene naturally overexpressed in several tumors. Besides its role as coactivator, it can exert several protumoral cytoplasmic actions. Autophagy was found to act either as a tumor suppressor during the early stages of tumor development, or as a protector of the tumor cell in later stages under hypoxic conditions. We found that RAC3 overexpression inhibits autophagy when induced by starvation or rapamycin and involves RAC3 nuclear translocation-dependent and -independent mechanisms. Moreover, hypoxia inhibits the RAC3 gene expression leading to the autophagy process, allowing tumor cells to survive until angiogenesis occurs. The interplay between RAC3, hypoxia, and autophagy could be an important mechanism for tumor progression and a good target for a future anticancer therapy. (Cancer Sci 2012; 103: 2064-2071 A utophagy is a highly regulated cellular process that serves to remove damaged proteins and organelles from the cell. It contributes to an array of normal and pathological processes, and has recently emerged as a key regulator of multiple aspects of cancer biology.Autophagy is not only triggered under nutrient deficiency, resulting in mTOR pathway inhibition, but also under cellular stress, or mitochondria or endoplasmic reticulum damage.(1) Several transcription factors can also induce autophagy, such as HIF-a and FoxoA1, which are involved in hypoxia and aging responses, respectively.(1) Autophagy and nuclear factorkappa B (NF-jB) share common signals and regulators; both are able to control each other through positive or negative feedback loops, thus ensuring homeostatic responses.(2) Moreover, kinases were also found to have positive or negative modulation on autophagy. Class I phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) (both involved in the mTOR pathway), p70S6K, and p38 (3) were associated with inhibitory effects, whereas ERK, death-associated protein kinase, and c-Jun N-terminal kinase were involved in positive modulation of autophagy. (4) The molecular mechanism by which autophagy takes place is complex and implicates several steps.(5) Interference at initiation could lead to the complete inhibition of autophagy, and blockage on maturation could result in an abnormal accumulation of immature autophagosomes.(6) In normal cells, these two scenarios could be pathological. However, the role of autophagy in cancer is not at all clear and is likely dependent on tumor type, stage, and genetic context. This complexity is illustrated by the fact that autophagy has a dual effect in tumorigenesis, either inhibiting it during the early stages or promoting it at later stages or during chemotherapy (5) in order to allow tumor maintenance.The gene RAC3 (AIB1, SRC-3, NCoA3) is a member of the nuclear receptor coactivator p160 family, together with SRC-1 and TIF-2.(7,8) Although it was first described as a coactivator of estrogen receptor and other steroid receptors, (8) we have previously found that RAC3 is also a NF-jB coactivator.(9) In any case, it has an intrinsic histone ace...

RAC3 more than a nuclear receptor coactivator: a key inhibitor of senescence that is downregulated in aging

“…In addition to our previous findings concerning the inhibitory role of RAC3 over apoptosis 5 , 35 and autophagy, 36 some recent works have demonstrated that RAC3 expression is necessary to maintain the pluripotency and self-renewal of stem cells. 37 , 38 , 39 The loss or downregulation of RAC3 is associated with differentiation of the stem cell to a mature cell type, 37 where the telomerase activity is expected to be silenced.…”

“… 46 In addition, RAC3 overexpression is an autophagy inhibitor. 36 Figure 2c shows that both H 2 O 2 and rapamycin induced the increase of acid vesicles, compatible with autophagosomes, but RAC3 overexpression shows a clear inhibitory effect. Therefore, inhibition of autophagy could be one mechanism through which RAC3 overexpression inhibits the premature senescence.…”

“… 24 , 41 , 42 Similar to hydrogen peroxide (H 2 O 2 ), 43 depending on the drug concentration and cell type, it can induce apoptosis, senescence or autophagy. 36 Therefore, we first investigated the dose and time required for treatment with each one of these stimuli in order to induce senescence in HEK293 cells.…”

“…HEK293 cells normally express limiting quantities of the RAC3. 5 , 36 We investigated the effect of RAC3 overexpression in senescence.…”

“…We have previously shown that RAC3 is an inhibitor of both apoptosis 5 , 35 and autophagy. 36 Although apoptosis involves cell death, autophagy not always does. In fact, the process involves first cell surviving through the elimination of damaged organelles or misfolding proteins.…”