The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts

Abstract

Cancer-associated fibroblasts (CAFs) play critical roles in cancer progression by regulating tumor cell proliferation, angiogenesis, and metastasis. Recent studies demonstrated that CAFs induce inhibitory immune cell infiltration and chemotherapy resistance in gastric cancer by activating the NF-κB signaling pathway to secrete IL6, IL8, and other inflammatory factors. Inhibition of the NF-κB signaling pathway in CAFs might be a potential therapeutic strategy in gastric cancer. However, how the NF-κB pathway is activated in CAFs remains unclear. We showed that mesenchymal stem cells (MSCs) differentiated into CAFs, induced by the exosomes derived from gastric cancer cells. During the process of differentiation from MSCs into CAFs, we showed that nuclear PKM2 expression was continuously upregulated and associated with NF-κB P65 acetylation, contributing to P65 nuclear retention in CAFs and constant transcription of IL-6, IL-8, and other inflammatory factors, thus promoting gastric cancer cell proliferation. We showed that NF-κB P65 acetylation was induced by P300. We showed that nuclear PKM2 was derived from exosomes of gastric cancer cell lines and the positive feedback loop induced by PKM2-P65 combination. It is also proved that P300 inhibitors can inhibit tumor proliferation in an AGS subcutaneous xenograft tumor model. Our study showed that gastric cancer cells influence the continuous activation of the NF-κB signaling pathway in CAFs by secreting gastric cancer exosomes containing PKM2, thus inducing abnormal metabolism and inflammation activation. This study provides a new therapeutic target for CAF normalization or deactivation strategies.

PARP1-PKM2 Axis Mediates Right Ventricular Failure Associated With Pulmonary Arterial Hypertension

“… 41 Finally, nuclear PKM2 is required for the expression of cMYC 42 and NF-κB P65 nuclear retention, contributing to abnormal energy metabolism and continuous activation of inflammatory signaling pathways. 43 In support of this model pinpointing PARP1 and PKM2 as integral pieces of a self-perpetuating metabolic-inflammatory vicious circle of tissue damage, we found that blocking PARP1 activity or nuclear PKM2 translocation reduces PARP1 and PKM2 abundance in cells and tissues. Accordingly, the beneficial effects of PARP1 inhibition on RV function in PAB animals were largely recapitulated by PKM2 cytosolic activation.…”

Metabolic Reprogramming Mediates Delayed Apoptosis of Human Neutrophils Infected With Francisella tularensis

“…Second, PKM2 has been linked to apoptosis resistance via its ability to phosphorylate and stabilize pro-survival BCL-2 family proteins ( 51 , 52 ). PKM2 also translocates into the nucleus to modulate NF-κB-dependent gene expression and may inhibit caspase-3 indirectly via effects on miR-143 ( 51 , 53 ). Our published data show that mitochondrial integrity is significantly prolonged by LVS infection, and in keeping with this, BAX mRNA and protein are diminished and BAX translocation to mitochondria is significantly delayed ( 22 , 24 ), but whether this is attributable to HK2-VDAC interactions at mitochondrial surfaces and/or phosphoinositide 3-kinase signaling remains to be determined.…”

HSP90/IKK‐rich small extracellular vesicles activate pro‐angiogenic melanoma‐associated fibroblasts via the NF‐κB/CXCL1 axis

“…Here, we found that melanoma cell–derived sEVs upregulated CXCL1 expression in CAFs through the IKK/IκB/NF‐κB signaling pathway, and blocking the IKK/IκB/NF‐κB signaling pathway remarkably attenuated the proangiogenic capability of CAFs. Previous studies had found that tumor cell–derived EVs could transfer M2 pyruvate kinase, latent membrane protein 1, and integrin beta‐like 1 into CAFs, leading to the persistent activation of the NF‐κB signaling pathway in CAFs 20‐23 . However, the mechanisms underlying NF‐κB signaling activation in CAFs induced by melanoma‐derived sEVs remained unclear.…”

“…Previous studies had found that tumor cell–derived EVs could transfer M2 pyruvate kinase, latent membrane protein 1, and integrin beta‐like 1 into CAFs, leading to the persistent activation of the NF‐κB signaling pathway in CAFs. 20 , 21 , 22 , 23 However, the mechanisms underlying NF‐κB signaling activation in CAFs induced by melanoma‐derived sEVs remained unclear. In this study, we discovered that hypoxia could promote the enrichment of the HSP90/p‐IKKα/β complex in melanoma‐derived sEVs.…”