Abstract
// Wei Dong 1 , Yunxia Zhao 2 , Hongxin Cao 3 , Zhinan Wu 1 and Jiajun Du 1 1 Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China 2 Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China 3 Department of Oncology, Shandong University Qilu Hospital, Shandong University, Jinan, China Correspondence to: Jiajun Du, email: dujiajun@sdu.edu.cn Wei Dong, email: dongwei318@163.com Keywords: metformin, insulin like growth factor receptor subtype 1 (IGF-1R), p53, anticancer therapy, lung adenocarcinoma cells Received: April 28, 2017 Accepted: September 20, 2017 Epub: October 06, 2017 ABSTRACT Research in recent years revealed that the antidiabetic drug metformin has some anticancer properties, and p53 plays an important role in the metformin-induced tumor inhibition. But less clear is the mechanism by which p53 status affects metformin mediated cancer cell responses. In this study, the effect of metformin on cancer cells with different p53 genotypes was investigated, and we found metformin could inhibit cancer cell proliferation especially in p53-deficient cells. So a paired isogenic non-small cell lung cancer cell lines H1299 p53 +/+ and H1299 p53 -/- was involved to explore the possible mechanisms. We detected the differences in cell proliferation and solid tumor formation induced by metformin, furthermore, the signaling transduction of insulin like growth factor-1 receptor (IGF-1R) was evaluated, which was essential in cancer transformation and progression. Our results indicated that p53 deficiency lead to more efficient inhibition of IGF-1R signaling transduction, receptor degradation and ubiquitination induced by metformin, which resulted in enhanced cell apoptosis and proliferation inhibition in vitro , and more significant solid tumor growth retardation and cancer cell death in vivo . Although more cell lines and multiple experiments were required to make a general conclusion, our study suggested the enhanced inhibition of IGF-1R signaling pathway contribute to the metformin’s selective toxicity in p53-deficient lung adenocarcinoma cells.
Highlights
The biguanide metformin is the most widely used treatment drug for type 2 diabetes
Our results indicated that p53 deficiency lead to more efficient inhibition of insulin like growth factor-1 receptor (IGF-1R) signaling transduction, receptor degradation and ubiquitination induced by metformin, which resulted in enhanced cell apoptosis and proliferation inhibition in vitro, and more significant solid tumor growth retardation and cancer cell death in vivo
The cell viability and IC50 of metformin were detected by PrestoBlue Cell Viability Assay, and we found that the p53 mutant and deleted type cancer cells (H520, H1975 and H1299) were less resistance to metformin induced antitumor effects, with statistically significant lower metformin half maximal inhibitory concentration (IC50) and cell viability curves (Figure 1A&1B)
Summary
The biguanide metformin is the most widely used treatment drug for type 2 diabetes. It is believed to exert its effect by reducing hepatic glucose production and increasing insulin sensitivity as well as glucose use by peripheral tissues [1]. Two types of distinct but not exclusive anticancer effect were concluded: first, by decreasing insulinemia and glycaemia, metformin could block PI3K/MAPK signaling pathway implicated in cell growth; second, through the activation of the AMPK pathway, metformin could directly act on cancer cells by targeting various pathways including tumor metabolism, inflammation, angiogenesis and cancer stem cells [3]. Functional p53 was crucial in the regulation of cell cycle, apoptosis and senescence in response to DNA damage, hypoxia, and oncogenic activation [6]. Recent reports have revealed www.impactjournals.com/oncotarget that p53 plays an important role in the metformininduced inhibition of proliferation and AMPK activation [3, 9, 10]. Data from present study demonstrated p53 knockdown or mutation has a negative effect on metformin-induced growth inhibition, senescence and apoptosis [11]. The possible mechanism by which p53 status influenced metformin mediated cellular responses is still an important question to be addressed
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