RETRACTED ARTICLE: Large tumor suppressor kinase 2 overexpression attenuates 5-FU-resistance in colorectal cancer via activating the JNK-MIEF1-mitochondrial division pathway

Abstract

Background 5-Fluorouracil (5-FU) is a standard treatment for colorectal cancer, but most patients develop 5-FU resistance. Here, we conducted experiments to identify an effective approach to augment 5-FU-based treatment in colorectal cancer in vitro. Methods SW480 cells were in the present study and treated with 5-FU. Besides, LATS2 adenovirus vectors were infected into SW480 cells. Western blotting, immunofluorescence and ELISA were used to evaluate cell death and mitochondrial function. Pathway blocker was used to verify the role of MAPK-JNK pathway in SW480 cell death. Results An obvious drop in large tumor suppressor kinase 2 (LATS2) expression was observed in SW480 cells after treatment with 5-FU. In addition, upregulation of LATS2 expression through infection with LATS2 adenovirus further increased the reduction of SW480 cell viability induced by 5-FU. Functional exploration showed that 5-FU treatment suppressed mitochondrial membrane potential, enhanced cyt-c release into the nucleus, induced an oxidative injury environment by promoting ROS production, and eventually upregulated Bax-related mitochondrial apoptosis. Besides, LATS2 overexpression in combination with 5-FU treatment further perturbed mitochondrial homeostasis, and this effect was achieved by elevating mitochondrial division. Mechanistically, LATS2 overexpression and 5-FU co-treatment amplified mitochondrial division by upregulating MIEF1 expression in a manner dependent on MAPK-JNK axis. Knockdown of MIEF1 using an siRNA-mediated loss of function assay and/or inhibition of the MAPK-JNK pathway using the specific inhibitor SP600125 abolished LATS2/5-FU-mediated deleterious effects on mitochondrial performance and SW480 cell viability. Conclusions In light of the above findings, LATS2 downregulation could be a potential mechanism of low response to 5-FU treatment. Overexpression of LATS2 to further disrupt mitochondrial function via the JNK-MIEF1 signalling pathway might be a method to optimize 5-FU-based chemotherapy.

5‐Fluorouracil resistance mechanisms in colorectal cancer: From classical pathways to promising processes

“…Mitochondrial division is a mechanism that leads to the production of fragments with increased ROS levels. A recent study focused on SW480, a CRC cell line corresponding to an early stage of CRC, and showed that 5‐FU resistance was induced by a reduction of mitochondrial division in relation with decreased expression of both mitochondrial elongation factor 1 and the large tumor suppressor kinase 2 (LATS2)‐Hippo pathway 38 …”

The Hippo Signaling Pathway in Drug Resistance in Cancer

“…Merlin re-expression in glioma cells confers 5-FU sensitivity, likely through downregulating cIAP1 and cIAP2 that inhibit caspase activity and apoptosis [ 96 ]. Overexpression of LATS2 in combination with 5-FU treatment elevates the expression mitochondrial elongation factor 1 (MIEF1) via c-Jun N-terminal kinase (JNK) pathway, thus amplifying fatal mitochondrial stress [ 89 ].…”

The Role of a Key Amino Acid Position in Species-Specific Proteinaceous dUTPase Inhibition

“…thymidylate synthase or dihydrofolate reductase) [15,16]. Due to the suboptimal response rate of the presently used drugs, development of novel anti-cancer strategies acting on the thymidylate synthesis route is of high significance [17]. The enzyme dUTPase is tightly connected to this pathway, as dUMP is the sole precursor of de novo deoxythymidine triphosphate (dTTP) biosynthesis [14].…”