Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma.

Zhou, Guisheng; Yu, Juehua; Wang, A.; Liu, S.-H.; Sinnett‐Smith, James; Wu, James X.; Sanchez, Robbi; Nemunaitis, John; Ricordi, C.; Brunicardi, F Charles

doi:10.2174/1566524016666151222145551

Cited by 15 publications

(7 citation statements)

References 51 publications

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“…Studies have shown that metformin facilitates the phosphorylation of AMPK indirectly through the action of the upstream kinase LKB1 [ 34 , 35 ]. In contrast to the known contribution of AMPK/LKB1 in metformin’s glucoregulatory activities, it remains unclear how metformins’ antiproliferative activity is regulated, and is still being debated [ 36 – 38 ]. A recent report indicated that metformin required AMPK, but not LKB1, to halt the proliferation of human non-small cell lung cancer cells [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer

et al. 2017

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Multiple drug resistant (MDR) malignancy remains a predictable and often terminal event in cancer therapy, and affects individuals with many cancer types, regardless of the stage at which they were originally diagnosed or the interval from last treatment. Protein biomarkers of MDR are not globally used for clinical decision-making, but include the overexpression of drug-efflux pumps (ABC transporter family) such as MDR-1 and BCRP, as well as HIF1α, a stress responsive transcription factor found elevated within many MDR tumors. Here, we present the important in vitro discovery that the development of MDR (in breast cancer cells) can be prevented, and that established MDR could be resensitized to therapy, by adjunct treatment with metformin. Metformin is prescribed globally to improve insulin sensitivity, including in those individuals with Type 2 Diabetes Mellitus (DM2). We demonstrate the effectiveness of metformin in resensitizing MDR breast cancer cell lines to their original treatment, and provide evidence that metformin may function through a mechanism involving post-translational histone modifications via an indirect histone deacetylase inhibitor (HDACi) activity. We find that metformin, at low physiological concentrations, reduces the expression of multiple classic protein markers of MDR in vitro and in preliminary in vivo models. Our demonstration that metformin can prevent MDR development and resensitize MDR cells to chemotherapy in vitro, provides important medical relevance towards metformin’s potential clinical use against MDR cancers.

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Section: Resultsmentioning

confidence: 99%

Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer

et al. 2017

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“…Our team demonstrated that metformin suppresses growth of PDAC cells via inhibition of PDX1 via a variety of adenosine monophosphate (AMP)-activated protein kinase (AMPK)-dependent and/or AMPKindependent mechanisms. We thus identified a potential novel mechanism by which metformin exerts its anticancer action through down-regulating PDX1 (25,26).…”

Section: Metformin Targets Pdx1 Via Inhibiting Erk Signalingmentioning

confidence: 99%

PDX1 associated therapy in translational medicine

Yu¹,

Liu²,

Sanchez³

et al. 2016

Ann. Transl. Med.

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis and a low median survival due to lack of the early and reliable detection and effective therapeutic options, despite improvements observed for many other cancers in last decade. Pancreatic and duodenal homeobox 1 (PDX1), which is a homeodomain-containing transcription factor and a key regulator for insulin gene expression, β cell maturation and proper β cell function maintenance in the pancreas. Our previous studies revealed that PDX1 promotes tumorigenesis and it is a promising therapeutic target for PDAC. For translational purposes, we developed three therapeutic platforms utilizing RNA interference (RNAi), gene therapy and small inhibitory drug targeting PDX1, and further validated them in PDAC preclinical models both in vitro and in vivo. These PDX1 targeted therapies significantly inhibited PDX1 expression in PDAC cells, ablated PDX1-expressing human PDAC xenograft tumor growth, and prolonged survival in the PDAC mouse models. The data from these preclinical studies proved the translational potentials of PDX1 targeted therapies in PDAC and suggest that the strategy of developing PDX1 targeted therapies would permit a rapid bench-to-bedside translation of other relevant gene therapies, which would eventually benefit the patients suffering from this deadly disease.

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“…There are currently ten clinical trials in progress to determine whether metformin might prolong life for patients with pancreatic cancer 53, 54 . For these reasons, we chose to study and metformin and demonstrated that it suppresses growth of PDAC cells via inhibition of PDX1 via a variety of adenosine monophosphate (AMP)-activated protein kinase (AMPK)-dependent and/or AMPK-independent mechanisms 55 . (Figure 1).…”

Section: Small Molecules Targeting Pdx1-targeted In Pdacmentioning

confidence: 99%

Pancreatic cancer actionable genes in precision medicine and personalized surgery

Liu

Sanchez

et al. 2017

The Surgeon

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Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with an overall 5-year survival rate less than 5% due to the poor early diagnosis and lack of effective therapeutic options. The most effective therapy remains surgery, however post-operative survival could be enhanced with effective adjuvant therapy. The massive information gained from Omics techniques on PDAC at the beginning of the 21st century is a remarkable accomplishment. However, the information gained from the omics data, including next generation sequencing data, has yet to successfully affect care of patients suffering with PDAC. Therefore, we propose the development of an actionable genomic platform that matches a patient’s PDAC clinically actionable genes with potential targeted adjuvant therapies. Using this platform, PDX1 has been identified PDX1 as a potential actionable gene for PDAC, therefore, RNAi therapy, gene therapy and small inhibitory drugs, all targeting PDX1, serve as potential targeted adjuvant therapies. Preclinical studies support the hypothesis that identification of PDAC actionable genes could permit translation of a patient’s genomic information into precision targeted adjuvant therapy for PDAC.

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Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma.

Cited by 15 publications

References 51 publications

Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer

Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer

PDX1 associated therapy in translational medicine

Pancreatic cancer actionable genes in precision medicine and personalized surgery

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