ROCK1 regulates glycolysis in pancreatic cancer via the c-MYC/PFKFB3 pathway

• Published in: Biochimica et biophysica acta. General subjects Vol. 1868; no. 10; p. 130669
• Main Authors: Pang, Shuyang, Shen, Yuting, Wang, Yanan, Chu, Xuanning, Ma, Lingman, Zhou, Yiran
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2024
• Subjects: Animals; Apoptosis; C-MYC; Cell Line, Tumor; Cell Movement; Cell Proliferation; cytoplasm; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Gemcitabine; Gene Expression Regulation, Neoplastic; genes; Glycolysis; Humans; luciferase; Male; metastasis; Mice; Mice, Nude; Pancreatic cancer; pancreatic neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; PFKFB3; Phosphofructokinase-2 - genetics; Phosphofructokinase-2 - metabolism; phosphorylation; precipitin tests; prognosis; protein kinases; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; rho-Associated Kinases - genetics; rho-Associated Kinases - metabolism; ROCK1; Signal Transduction; therapeutics; C-MYC; Glycolysis; PFKFB3; ROCK1; Pancreatic cancer
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2024.130669

Dysregulation of Rho-associated coiled coil-containing protein kinases (ROCKs) is involved in the metastasis and progression of various malignant tumors. However, how one of the isomers, ROCK1, regulates glycolysis in tumor cells is incompletely understood. Here, we attempted to elucidate how ROCK1 influences pancreatic cancer (PC) progression by regulating glycolytic activity. The biological function of ROCK1 was analyzed in vitro by establishing a silenced cell model. Coimmunoprecipitation confirmed the direct binding between ROCK1 and c-MYC, and a luciferase reporter assay revealed the binding of c-MYC to the promoter of the PFKFB3 gene. These results were verified in animal experiments. ROCK1 was highly expressed in PC tissues and enriched in the cytoplasm, and its high expression was associated with a poor prognosis. Silencing ROCK1 inhibited the proliferation and migration of PC cells and promoted their apoptosis. Mechanistically, ROCK1 directly interacted with c-MYC, promoted its phosphorylation (Ser 62) and suppressed its degradation, thereby increasing the transcription of the key glycolysis regulatory factor PFKFB3, enhancing glycolytic activity and promoting PC growth. Silencing ROCK1 increased gemcitabine (GEM) sensitivity in vivo and in vitro. ROCK1 promotes glycolytic activity in PC cells and promotes PC tumor growth through the c-MYC/PFKFB3 signaling pathway. ROCK1 knockdown can inhibit PC tumor growth in vivo and increase the GEM sensitivity of PC tumors, providing a crucial clinical therapeutic strategy for PC. •Rock1 promotes the proliferation and metastasis of pancreatic cancer cells in vitro/ vivo.•Rock1/c-MYC axis affects the proliferation of pancreatic cancer by regulating the level of glycolysis.•Rock1 elevates the the growth activity of pancreatic cancer by promoting the stability of c-MYC protein.