AGR2 silencing contributes to metformin‑dependent sensitization of colorectal cancer cells to chemotherapy

Abstract

There is growing epidemiological evidence indicating an association between diabetes mellitus and the increased incidence of colorectal cancer (CRC). The preferred initial and most widely used pharmacological agent for the treatment of type 2 diabetes is metformin, which in parallel reduces the risk of CRC and improves patient prognosis. AMP-activated protein kinase (AMPK) appears to be tightly associated with the beneficial metabolic effects of metformin, serving as a cellular energy sensor activated in response to a variety of conditions that deplete cellular energy levels. Such conditions include nutrient starvation (particularly glucose), hypoxia and exposure to toxins that inhibit the mitochondrial respiratory chain complex. The aim of the present study was to determine the effect of metformin on CRC cell lines, with different levels of anterior gradient 2 (AGR2) expression, exposed to 5-fluorouracil (5-FU) and oxaliplatin, alone or in combination with metformin. AGR2 has recently emerged as a factor involved in colon carcinogenesis. In AGR2-knockout cells, markedly higher levels of phosphorylated-AMPK were observed in comparison with control cells transfected with GFP-scrambled guide RNA, which indicated that the presence of AGR2 may interfere with the metformin-dependent activation of AMPK. In addition, metformin in combination with 5-FU and oxaliplatin induced ROS production and attenuated autophagy. This effect was enhanced in AGR2-knockout cells.

The anterior gradient homologue 2 (AGR2) co-localises with the glucose-regulated protein 78 (GRP78) in cancer stem cells, and is critical for the survival and drug resistance of recurrent glioblastoma: in situ and in vitro analyses

“…Previously, repression of AGR2 via targeting exon 7 or exon 8 in glioblastoma standard cell lines showed disruptions in the cell cycle, cell growth, migration, and cell invasion [ 41 , 83 , 84 ]. In colorectal cancer cells, AGR2 exon 2 knockout was shown to be crucial for protein-mediated cell adhesion, and resulted in the increase of reaction oxygen species production [ 85 ]. This suggests that targeting different regions of AGR2 results in different responses that may also be cell line dependent.…”

“…Knocking down AGR2 using siRNA against AGR2 exon 2B in the primary cell lines had partially synergistic effects with the glioblastoma-associated drugs temozolomide and irinotecan. AGR2 knockout, in combination with other drugs, was previously shown to be effective in inhibiting the growth of different cell line models [ 85 – 88 ]. To the best of our knowledge, this is the first study to show observations related to the effect of siRNA against AGR2 exon 2 in combination with either temozolomide or irinotecan.…”

Biomarker discovery for practice of precision medicine in hypopharyngeal cancer: a theranostic study on response prediction of the key therapeutic agents

“…The potential of these 4 molecules as a novel drug target also has been shown in a variety of studies: An accumulated knowledge on AGR2, PDE4D, NINJ2 and CDC25B have accelerated the drug discovery targeting these molecules in the other cancers. Despite of the extensive efforts, none of the clinically available target drugs, however, have been developed yet [ 50 – 54 ]. The research on drug discovery targeting the 4 molecules remain rudimentary.…”

AGR2: The Covert Driver and New Dawn of Hepatobiliary and Pancreatic Cancer Treatment

“…Additionally, the emergence of cancer drug resistance is intricately linked to the UPR triggered by ERS, encompassing signaling pathways that induce resistance in solid tumor cells, including anti-apoptotic signaling, protective autophagy, and non-coding RNAs [123]. Pancreatic cancer [124], non-small cell lung cancer [125], colon cancer [126], and breast cancer [127] exhibit drug resistance via AGR2 involvement. In pancreatic cancer, AGR2 within cancer cells exerts a protective effect post-treatment with gemcitabine chemotherapeutic agents [16].…”