title: Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo.
abstract: We observed a co-upregulation of the insulin-like growth factor receptor (IGF-1R)/AKT/mammalian target of rapamycin (mTOR) [InAT] axis and the mevalonate-isoprenoid biosynthesis (MIB) pathways in colorectal cancer stem cells (CSCs) in an unbiased approach. Hence, we hypothesized that the InAT axis might regulate the MIB pathway to govern colorectal CSCs growth. Stimulation (IGF-1) or inhibition (IGF-1R depletion and pharmacological inhibition of IGF-1R/mTOR) of the InAT axis produced induction or attenuation of CSC growth as well as expression of CSC markers and self-renewal factors respectively. Intriguingly, activation of the InAT axis (IGF-1) caused significant upregulation of the MIB pathway genes (both mRNA and protein); while its inhibition produced the opposite effects in colonospheres. More importantly, supplementation with dimethylallyl- and farnesyl-PP, MIB metabolites downstream of isopentenyl-diphosphate delta isomerase (IDI), but not mevalonate and isopentenyl-pp that are upstream of IDI, resulted in a near-complete reversal of the suppressive effect of the InAT axis inhibitors on CSCs growth. The latter findings suggest a specific regulation of the MIB pathway by the InAT axis distal to the target of statins that inhibit 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). Effects of IGF-1R inhibition on colonic CSCs proliferation and the MIB pathway were confirmed in an 'in vivo' HCT-116 xenograft model. These observations establish a novel mechanistic link between the InAT axis that is commonly deregulated in colorectal cancer and the MIB pathway in regulation of colonic CSCs growth. Hence, the InAT-MIB corridor is a novel target for developing paradigm shifting optimum anti-CSCs therapies for colorectal cancer.
authors.affiliation: Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Chetna
authors.initials: C
authors.lastname: Sharon
authors.affiliation: Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Somesh
authors.initials: S
authors.lastname: Baranwal
authors.affiliation: Hunter Holmes McGuire VA Medical Center, Richmond, VA, USA.
authors.forename: Nirmita J
authors.initials: NJ
authors.lastname: Patel
authors.affiliation: Hunter Holmes McGuire VA Medical Center, Richmond, VA, USA.|Department of Medicine, Division of Gastroenterology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rodriguez-Agudo
authors.affiliation: Hunter Holmes McGuire VA Medical Center, Richmond, VA, USA.|Department of Medicine, Division of Gastroenterology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Pandak
authors.affiliation: John D. Dingell VAMC, Detroit, MI, USA.
authors.forename: Adhip P N
authors.initials: AP
authors.lastname: Majumdar
authors.affiliation: Hunter Holmes McGuire VA Medical Center, Richmond, VA, USA.|Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.|Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Krystal
authors.affiliation: Hunter Holmes McGuire VA Medical Center, Richmond, VA, USA.|Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.|Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Bhaumik B
authors.initials: BB
authors.lastname: Patel
mesh_terms: D000818:Animals; D017209:Apoptosis; D019748:Carbon-Carbon Double Bond Isomerases / Q000235:genetics; D049109:Cell Proliferation / Q000502:physiology; D015179:Colorectal Neoplasms / Q000473:pathology*; D045325:HCT116 Cells; D045782:Hemiterpenes / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000378:metabolism / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D012717:Sesquiterpenes / Q000378:metabolism / Q000494:pharmacology; D018874:Spheroids, Cellular; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013729:Terpenes / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D045782:Hemiterpenes; D009943:Organophosphorus Compounds; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D012717:Sesquiterpenes; D013729:Terpenes; C043060:3,3-dimethylallyl pyrophosphate; C004808:farnesyl pyrophosphate; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D019748:Carbon-Carbon Double Bond Isomerases; C021453:isopentenyldiphosphate delta-isomerase; D008798:Mevalonic Acid
keywords: cancer stem cells; insulin-like growth factor-1 receptor; isoprenoids; mTOR; mevalonate pathway