Disruption of IGF-1R signaling increases TRAIL-induced apoptosis: a new potential therapy for the treatment of melanoma
Authors: Thomas B Karasic
Vladimir N Ivanov
Tom K Hei
Journal: Experimental cell research (2010)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: cancer cells; apoptosis resistance; genetic mechanisms; epigenetic mechanisms; Insulin-like Growth Factor-1 Receptor (IGF-1R)
Affiliations: Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

Abstract:  Resistance of cancer cells to apoptosis is dependent on a balance of multiple genetic and epigenetic mechanisms, which up-regulate efficacy of the surviving growth factor-receptor signaling pathways and suppress death-receptor signaling pathways. The Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling pathway is highly active in metastatic melanoma cells by mediating downstream activation of PI3K-AKT and MAPK pathways and controlling general cell survival and proliferation. In the present study, we used human melanoma lines with established genotypes that represented different phases of cancer development: radial-growth-phase WM35, vertical-growth-phase WM793, metastatic LU1205 and WM9 [1]. All these lines have normal NRAS. WM35, WM793, LU1205 and WM9 cells have mutated BRAF (V600E). WM35 and WM9 cells express normal PTEN, while in WM793 cells PTEN expression is down-regulated; finally, in LU1205 cells PTEN is inactivated by mutation. Cyclolignan picropodophyllin (PPP), a specific inhibitor of IGF-1R kinase activity, strongly down-regulated the basal levels of AKT activity in WM9 and in WM793 cells, modestly does so in LU1205, but has no effect on AKT activity in the early stage WM35 cells that are deficient in IGF-1R. In addition, PPP partially down-regulated the basal levels of active ERK1/2 in all lines used, highlighting the role of an alternative, non-BRAF pathway in MAPK activation. The final result of PPP treatment was an induction of apoptosis in WM793, WM9 and LU1205 melanoma cells. On the other hand, dose-dependent inhibition of IGF-1R kinase activity by PPP at a relatively narrow dose range (near 500 nM) has different effects on melanoma cells versus normal cells, inducing apoptosis in cancer cells and G2/M arrest of fibroblasts. To further enhance the pro-apoptotic effects of PPP on melanoma cells, we used a combined treatment of TNF-Related Apoptosis-Inducing Ligand (TRAIL) and PPP. This combination substantially increased death by apoptosis for WM793 and WM9 cells, but did so only modestly for LU1205 cells with very high basal activity of AKT. The ultimate goal of this direction of research is the discovery of a new treatment method for highly resistant human metastatic melanomas. Our findings provide the rationale for further preclinical evaluation of this novel treatment. 

Retracted: No

PubPeer comments:
 Retracted [11 January 2021] . ---------------------------------- We, the Editors and Publisher of the journal Artificial Cells, Nanomedicine, and Biotechnology, have retracted the following article: Wei Lu, Chao Yang, Peng Du, Jun-Li Zhang Jia-Cheng Zhang (2019) Expression tendency and prognostic value of TCF21 in hepatocellular carcinoma. Artificial Cells, Nanomedicine, and Biotechnology, 47:1, 1466u20131470, DOI: https: doi.org 10.1080 21691401.2019.1601102 It has come to our attention that the full authorship list and affiliations for this manuscript were changed after the article was submitted. We have contacted the authors for an explanation, but we have not received a response within the requested timeframe. In addition, the article content significantly overlaps with a manuscript previously submitted to the journal, with a different authorship team listed. As determining authorship is core to the integrity of published work, we are retracting the article. All authors listed in this publication have been sent notification. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as u2018Retractedu2019. ,