HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer

Abstract

Dysfunctional mitochondria have been shown to enhance cancer cell proliferation, reduce apoptosis, and increase chemoresistance. Chemoresistance develops in nearly all patients with colorectal cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. However, the effect of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission on chemoresistance in colorectal cancer is unclear. Here, we found that the release of high-mobility group box 1 protein (HMGB1) in conditioned medium from dying cells by chemotherapeutic drugs and resistant cells, which triggered Drp1 phosphorylation via its receptor for advanced glycation end product (RAGE). RAGE signals ERK1/2 activation to phosphorylate Drp1 at residue S616 triggerring autophagy for chemoresistance and regrowth in the surviving cancer cells. Abolishment of Drp1 phosphorylation by HMGB1 inhibitor and RAGE blocker significantly enhance sensitivity to the chemotherapeutic treatment by suppressing autophagy. Furthermore, patients with high phospho-Drp1Ser616 are associated with high risk on developing tumor relapse, poor 5-year disease-free survival (DFS) and 5-year overall survival (OS) after neoadjuvant chemoradiotherapy (neoCRT) treatment in locally advanced rectal cancer (LARC). Moreover, patients with RAGE-G82S polymorphism (rs2070600) are associated with high phospho-Drp1Ser616 within tumor microenvironment. These findings suggest that the release of HMGB1 from dying cancer cells enhances chemoresistance and regrowth via RAGE-mediated ERK/Drp1 phosphorylation.

Subcellular localization of HMGB1 in colorectal cancer impacts on tumor grade and survival prognosis

“…Interestingly, nuclear-positive HMGB1 expression had an opposite outcome on survival prognosis, as CRC patients with strongly positive nuclear HMGB1 expression had a better prognosis than other patients. Previous studies involving different cancers concluded that HMGB1 plays a paradoxical role in promoting or suppressing cancer 3 , 5 – 10 . This is the first time that HMGB1 has been found to play both positive and negative roles in the same study population.…”

“…High-mobility group box-1 (HMGB1) protein, also known as amphoterin or HMG1, was discovered in calf thymus and named according to its high electrophoretic mobility in polyacrylamide gels 3 . The biological function of HMGB1 depends on its subcellular localization and expression 4 , whereby HMGB1 can play a paradoxical role in promoting or suppressing cancer during the progression of malignant tumors 3 , 5 – 10 . Inside the nucleus, HMGB1 is a highly conserved chromosomal protein engaged in DNA repair, transcription and genome stability 3 , 5 .…”

Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer

“…Total lysates (30 µg) were separated via 6%-12% SDS-PAGE, transferred onto PVDF membranes (Millipore, MA, USA) [26,27], blocked with 5% nonfat milk, incubated with specific antibodies (in 1% non-fat milk) overnight at 4 • C, and probed with HRP-conjugated secondary antibodies. The blot membrane was then incubated with Immobilon Western Chemiluminescent HRP Substrate (Millipore, MA, USA), analyzed by an ImageQuant™ LAS 4000 biomolecular imager (GE Healthcare, Amersham, UK), processed with Adobe Photoshop, and quantified by using ImageJ software (NIH, MD, USA).…”

Receptor for Advanced Glycation End Products Acts as a Fuel to Colorectal Cancer Development

“…Furthermore, Gly82Ser, which is the single-nucleotide polymorphism (SNP) of RAGE (rs2070600), enhances ligand binding to boost the downstream signaling pathway, which is associated with amplified risk of numerous cancer types; particularly, the frequency of this polymorphism is much higher in late-stage CRC patients (57,58). Thus, polymorphism of RAGE can affect its function.…”

“…Moreover, it has been shown that high phospho-Drp1Ser616 in CRC patients is related to a high possibility of developing tumor relapse. Moreover, RAGE-G82S polymorphism (rs2070600) has high ligand affinity and is related to high phospho-Drp1Ser616 in tumor microenvironment (57) (Figure 4).…”