Fig. 2

The biological mechanism of chronic stress affecting cancer cells. A Chronic stress promotes the stem cell characteristics in cancer cells. Chronic stress-induced E activates LDHA, promotes glycolysis, and leads to lactate secretion, this enhances the interaction between USP28 and MYC, which promotes stem cell-like-associated genes expression via SLUG. Chronic stress-induced GCs promote β-catenin expression through the interaction of GRP78 with LRP5. GCs also downregulate miR-346 and miR-493, which in turn upregulate Cyclin D1 and accelerate the cell cycle. In addition, GCs promote GRs-dependent nuclear accumulation and TEAD4 transcriptional activation, promoting the maintenance of CSCs. B Chronic stress accelerates cancer cell metastasis. Chronic stress-induced β-ARs signaling activates FAK via cAMP/PKA, which induces extracellular matrix remodeling via Erk1/2-MMP; Src is also activated by cAMP/PKA, and Y419 phosphorylation of Src amplifies HIF1α and MYC, further inducing hTERT overexpression in the nucleus. hTERT activates SLUG and in turn upregulates metastasis-related genes. β-ARs also promotes β-catenin expression and nuclear localization through PI3K/AKT and increases SLUG promoter activity. NE-induced downregulation of miR-337-3p activates STAT3. β-ARs activates MMP7 and releases HB-EGF to activate EGFR, whereas MAOA can target β2-ARs to reverse these processes. In addition, β-ARs promotes neuroendocrine phenotypic transformation and metastasis through MACC1 upregulation, which binds directly to SYP via c-Jun. GRs contribute to increased ROR1. In addition, GRs increase CTGF expression via PI3K/SGK/Nedd4l-Smad2 and promotes lung metastasis. GRs localize to the CDK1 promoter in nucleus and stimulate CDK1 through epigenetic regulation. C Chronic stress promotes angiogenesis. β-ARs activates CREB and STAT3 via cAMP/PKA, STAT3 translocates to the nucleus and stimulates VEGF and MMP2/9 transcription, CREB targets HDAC2 activation, which epistemically represses TSP1. In addition, PPARγ inhibits VEGF by suppressing ROS, while β-ARs signaling reverses the effect of PPARγ on VEGF/FGF2. D Chronic stress promotes DNA damage accumulation and anti-apoptosis. β-ARs mediates Src/FAK and BAD anti-apoptotic pathways by PKA, BAD-S112 phosphorylation and FAK-Y397 phosphorylation gain resistance to apoptosis. GCs stabilize CFLARL through GMEB1-USP40 interaction, inhibit pro-CASP8 activation, thereby inhibiting apoptosis. SGK1, a key downstream effector of Ras, promotes glucose-mediated carbon flux into multiple metabolic pathways to inhibit oxidation by GLUT1 activation; in addition, Ras blocks apoptosis by reducing PHLPP1, which activates p38 MAPK to promote apoptosis. Elevated NE/E and GCs increase MDM2 activity and decrease p53 function via SGK1 and ARRB1, β-ARs and GRs also stimulate the production of ROS and RNS, ultimately leading to DNA damage accumulation