Metformin inhibition of colorectal cancer cell migration is associated with rebuilt adherens junctions and FAK downregulation

Amable, Gastón; Martínez‐León, Eduardo; Picco, María Elisa; Nemirovsky, Sergio I.; Rey, Osvaldo

doi:10.1002/jcp.29677

Cited by 10 publications

(19 citation statements)

References 105 publications

(140 reference statements)

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“…As metastasis is the major cause of death in CRC patients, we explored the effect of M + P on different metastasis-related cellular events. As expected from previous reports by other groups 57 , 69 , 70 both Met and Prop affected CRC cells migration in vitro. Noteworthy, combined treatment caused significantly stronger migration impairment for all the cell types analyzed.…”

Section: Discussionsupporting

confidence: 91%

Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment

Anselmino

Baglioni

Malizia

et al. 2021

Sci Rep

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Drug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher. Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat. For both tumor types, available treatments are generally associated to severe side effects. In our work, we explored the effect of combining metformin and propranolol, two repositioned drugs, in both tumor types. We demonstrate that treatment affects viability, epithelial-mesenchymal transition and migratory potential of CRC cells as we described before for TNBC. We show that combined treatment affects different steps leading to metastasis in TNBC. Moreover, combined treatment is also effective preventing the development of 5-FU resistant CRC. Our data suggest that combination of metformin and propranolol could be useful as a putative adjuvant treatment for both TNBC and CRC and an alternative for chemo-resistant CRC, providing a low-cost alternative therapy without associated toxicity.

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Section: Discussionsupporting

confidence: 91%

Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment

Anselmino

Baglioni

Malizia

et al. 2021

Sci Rep

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“…Metformin treatment was also associated with an increase in the intracellular levels of p120-catenin, a result consistent with the observation that β-catenin drives the transcription of forkhead/winged-helix transcription factors (Savage et al, 2010), which in turn down-regulate p120-catenin transcription (Mortazavi et al, 2010;Pham et al, 2017). In addition, metformin promoted the redistribution of p120-catenin to the plasma membrane where co-localized with E-cadherin/β-catenin, suggesting that metformin promotes the novo formation of AJs (Amable et al, 2020). Nevertheless, Amable et al (2020), did not examine whether N-cadherin, which is expressed in the cell lines SW-480 and HT-29 employed in those studies (Yan et al, 2015;Ye et al, 2017) was down regulated in response to metformin.…”

Section: Metformin E-cadherin Fak and Metforminsupporting

confidence: 86%

“…In addition, metformin promoted the redistribution of p120-catenin to the plasma membrane where co-localized with E-cadherin/β-catenin, suggesting that metformin promotes the novo formation of AJs (Amable et al, 2020). Nevertheless, Amable et al (2020), did not examine whether N-cadherin, which is expressed in the cell lines SW-480 and HT-29 employed in those studies (Yan et al, 2015;Ye et al, 2017) was down regulated in response to metformin.…”

Section: Metformin E-cadherin Fak and Metforminmentioning

confidence: 98%

“…Recent studies employing metformin concentrations compatible with the ones in the colon after oral administration of therapeutic doses of this drug indicate that metformin not only promoted the plasma membrane localization of β-catenin and E-cadherin but also their colocalization to de novo formed puncta along the length of CRC-derived cells contacting membranes (Amable et al, 2020). The plasma membrane redistribution of E-cadherin in response to metformin treatment was accompanied by its phosphorylation at Ser 838/840 , modifications associated to E-cadherin/β-catenin binding and increased interaction stability between both proteins (McEwen et al, 2014).…”

Section: Metformin E-cadherin Fak and Metforminmentioning

confidence: 99%

“…Former reports indicated that metformin inhibited FAK phosphorylation in ovarian (Erices et al, 2017) and prostatic cancer cells (Yu et al, 2017) whereas a more recent study showed that, in CRC-derived cells, metformin inhibited FAK catalytic activity and ERK-dependent FAK Ser 910 phosphorylation (Hunger-Glaser et al, 2003;Hunger-Glaser et al, 2004;Jiang et al, 2007), a modification associated with paxillin/FAK interaction, cell spreading and migration (Chu et al, 2011;Luo et al, 2019;Vincent and Settleman, 1997). Metformin-mediated inhibition of FAK led to FAs structural changes including a reduction in their numbers and increase in their size (Amable et al, 2020), very likely through a modification of FAs turnover (Ilic et al, 1995;Iwanicki et al, 2008;Kim and Wirtz, 2013;Plotnikov et al, 2012), changes that were followed by cellular migration inhibition (Amable et al, 2020).…”

Section: Metformin E-cadherin Fak and Metforminmentioning

confidence: 99%

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Metformin and colorectal cancer

Amable¹,

Martínez-León²,

Picco³

et al. 2022

Biocell

Self Cite

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Colorectal cancer (CRC) is one of the main causes of cancer-related mortality in the developed world despite recent developments in detection and treatment. Several epidemiological studies indicate that metformin, a widely prescribed antidiabetic drug, exerts a protective effect on different cancers including CRC. Furthermore, a recent double-blind placebo-controlled, randomized trial showed that metformin significantly decreased colorectal adenoma recurrence. Studies exploring the mechanism of action of metformin in cells derived from different types of cancers reported many effects including respiratory chain complex 1 inhibition, Akt phosphorylation inhibition, ATP depletion, PKA activation and Wnt signaling inhibition. However, many of these results were obtained employing metformin at concentrations several fold higher than those achieved in target tissues in diabetic patients receiving therapeutic recommended doses of metformin. In contrast, recent studies obtained with metformin at concentrations compatible with those detected in human intestines revealed that metformin elicit responses that target β-catenin, PI3K/Akt, E-cadherin, p120-catenin and focal adhesion kinase which are key molecules and signaling pathways associated to colorectal cancer development. This brief review revisit several know aspects as well as novel ones on the effects of metformin on cancer cells.

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Effects of down‐regulated carbonic anhydrase 8 on cell survival and glucose metabolism in human colorectal cancer cell lines

Wu,

Yu,

Chen

et al. 2024

Cell Biochemistry & Function

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Carbonic anhydrase 8 (CA8) is a member of the α‐carbonic anhydrase family but does not catalyze the reversible hydration of carbon dioxide. In the present study, we examined the effects of CA8 on two human colon cancer cell lines, SW480 and SW620, by suppressing CA8 expression through shRNA knockdown. Our results showed that knockdown of CA8 decreased cell growth and cell mobility in SW620 cells, but not in SW480 cells. In addition, downregulated CA8 resulted in a significant decrease of glucose uptake in both SW480 and SW620 cells. Interestingly, stable downregulation of CA8 decreased phosphofructokinase‐1 expression but increased glucose transporter 3 (GLUT3) levels in SW620 cells. However, transient downregulation of CA8 fails to up‐regulate GLUT3 expression, indicating that the increased GLUT3 observed in SW620‐shCA8 cells is a compensatory effect. In addition, the interaction between CA8 and GLUT3 was evidenced by pull‐down and IP assays. On the other hand, we showed that metformin, a first‐line drug for type II diabetes patients, significantly inhibited cell migration of SW620 cells, depending on the expressions of CA8 and focal adhesion kinase. Taken together, our data demonstrate that when compared to primary colon cancer SW480 cells, metastatic colon cancer SW620 cells respond differently to downregulated CA8, indicating that CA8 in more aggressive cancer cells may play a more important role in controlling cell survival and metformin response. CA8 may affect glucose metabolism‐ and cell invasion‐related molecules in colon cancer, suggesting that CA8 may be a potential target in future cancer therapy.

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Metformin inhibition of colorectal cancer cell migration is associated with rebuilt adherens junctions and FAK downregulation

Cited by 10 publications

References 105 publications

Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment

Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment

Metformin and colorectal cancer

Effects of down‐regulated carbonic anhydrase 8 on cell survival and glucose metabolism in human colorectal cancer cell lines

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