STAT3 transcriptional factor activated by reactive oxygen species induces IL6 in starvation-induced autophagy of cancer cells

Abstract

Autophagy is one of the survival processes of cancer cells, especially in stressful conditions such as starvation, hypoxia and chemotherapeutic agents. However, its roles in tumor survival have not yet been fully elucidated. Here, we found for the first time that JAK2/STAT3 was activated in HeLa cells when they were starved or treated with rapamycin. STAT3 activation was associated with autophagic processes, because it was completely inhibited by 3-methyladenine, partially inhibited by knockdown of molecules associated with autophagic processes and blocked by antioxidants, DPI, a Nox inhibitor and knockdown of p22 phox, indicating that ROS generated by Nox that was activated during autophagic processes activated JAK2/STAT3 pathway. Activated STAT3 directly bound to IL6 promoter and increased IL6 mRNA and protein secretion. Finally, the conditioned media, which included IL6, from starved HeLa cells promoted cancer cell survival in both normal and starved conditions, confirmed by clonogenic, proliferation and cell death assays. These data together indicate that the autophagic process in cancer cells can contribute to their survival by JAk2/STAT3 activation and subsequent secretion of growth factors.

NF-κB and STAT3 cooperatively induce IL6 in starved cancer cells

“…We recently observed that Jak2/STAT3 pathway was activated in both starvation and rapamycin treatment of cancer cells. However, IL6 was induced only in starved cells but not in rapamycin-treated cells (Yoon et al, 2010). As there was clear difference between the two models of autophagy, we were able to find in the present work that NF-kB was activated only in starvation, thus contributing to full IL6 induction in collaboration with activated STAT3.…”

“…In the previous study, we found that Jak2/STAT3 was activated in amino-acid-and serum-deprived cancer cells, as well as rapamycin-treated cancer cells (Figure 1a), which was totally dependent on ROS produced by NADPH oxidase enzymes that were activated during early autophagic processes (Yoon et al, 2010). Activated STAT3 contributed to the induction of IL6 cytokine mRNA and its protein secretion only in starved cancer cells but not in rapamycin-treated cancer cells (Figures 1b and c), indicating that additional signals for full induction of IL6 were lacking in rapamycin-induced autophagy of cancer cells.…”

“…Amino-acid and serum deprivation drives HeLa cells to autophagic processes (Yoon et al, 2010), therefore, it is highly possible that autophagic processes have a role in NF-kB activation. In order to elucidate the possibility, HeLa cells stably expressing either Beclin1 shRNA and Atg5 shRNA, or Beclin1 shRNA and Vps34 shRNA were established.…”

“…Target proteins transcribed by activated STAT3 are implicated in fundamental events of tumor development, including its proliferation, survival, invasion and angiogenesis (Groner et al, 2008). Recent findings show that STAT3 can also be activated by reactive oxygen species (ROS) generated by NADPH oxidase (Lee et al, 2007;Souza et al, 2009;Yoon et al, 2010).…”

Molecular pathogenesis of lymphomas of mucosa-associated lymphoid tissue—from (auto)antigen driven selection to the activation of NF-κB signaling

“…The presence of excessive ROS can cause fatal cellular lesions by damaging cellular proteins, lipids and DNA [35]. ROS are associated with various transcription factors, such as NF-B [36], activator protein-1 (AP-1) [37], hypoxiainducible factor-1 [38] and signal transducer and activator of transcription 3 (STAT3) [39], which are involved in inflammation, cellular transformation and tumor biology. Furthermore, ROS also control the expression of various tumor suppressor genes, such as phosphatase and tensin homolog (PTEN) [40].…”