Poster Presentation 12th International Meeting on AMPK 2023

Metformin induces an AMPK-independent NEAT1 isoform switch in colorectal cancer cells (#73)

Nadine E Smith 1 , Ayla Orang 1 , Kaitlin R Morrison 1 , Shashikanth Marri 1 , Michael Z Michael 1 , Janni Petersen 1
  1. Flinders University, Bedford Park, SA, Australia

Approximately 150 million people worldwide take metformin for the management of Type II Diabetes Mellitus [1]. Metformin can reduce colorectal cancer (CRC) incidence, although the mechanisms of action are not fully understood. The lncRNA NEAT1 is dysregulated in many cancers, especially CRC [2]. The single exon gene produces two isoforms, NEAT1_1 and NEAT1_2, through alternative 3′-end processing, with the latter providing the essential scaffold for nuclear paraspeckle formation [3]. It was previously thought that NEAT1_1 only exists to keep the NEAT1 locus active for rapid paraspeckle formation [4]. However, a recent glycolysis-enhancing (Warburg) function for NEAT1_1, contributing to cancer cell proliferation, has been demonstrated [5]. Prior studies suggest NEAT1 can act in either a tumour-suppressive or oncogenic manner, depending on the isoform expressed [2]. Due to their overlapping 5’-ends, independent quantification of NEAT1 isoforms has proven challenging. We have developed a novel technique for the quantification of the individual NEAT1 isoforms. We use this to demonstrate that therapeutic doses of metformin drive a NEAT1 isoform switch to induce nuclear paraspeckle formation in colorectal HCT116 and LIM1215 cancer cells when grown at physiological glucose levels. It is widely accepted that metformin activates AMPK, in part through the inhibition of mitochondrial complex 1. In this study, the metformin induced NEAT1 isoform switch still occurs in AMPK ⍺1 and ⍺2 null HCT116 cell lines. Regardless, the metformin-induced isoform switch and subsequent paraspeckles may promote cell survival under stress.

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