title: Modulation of glycolysis and lipogenesis by novel PI3K selective molecule represses tumor angiogenesis and decreases colorectal cancer growth.
abstract: Phosphatidylinositol 3-kinase (PI3K) pathway drives cancer progression through direct regulation of most oncogenic properties. Here, we report that PI3K pathway signaling up-regulates cancer cell proliferation, metastasis and angiogenesis through modulation of cancer metabolism. These oncogenic metabolic processes were disrupted, by a novel PI3K inhibitor, 3-Dihydro-2-(naphthalene-1-yl) quinazolin-4(1H)-one (DHNQ) in colon cancer cells. DHNQ inhibited the Warburg effect and lipid synthesis by reducing gene expression of glycolytic and lipogenesis regulatory enzymes. This downregulation at gene level by DHNQ inhibited metabolic flux to repress proliferation, migration and invasion characteristics of colon cancer. Furthermore, the metabolic attenuation caused repression of in vitro/in vivo angiogenesis providing new insights in PI3K regulated angiogenesis via metabolic alterations. Our results suggest that multifaceted targeting of oncogenic metabolism by their upstream PI3K regulatory signaling may be an effective cancer treatment approach.
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Aashiq
authors.initials: A
authors.lastname: Hussain
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Asif Khurshid
authors.initials: AK
authors.lastname: Qazi
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Nagaraju
authors.initials: N
authors.lastname: Mupparapu
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Guru
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Parduman Raj
authors.initials: PR
authors.lastname: Sharma
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Shashank Kumar
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Paramjit
authors.initials: P
authors.lastname: Singh
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Mohd Jamal
authors.initials: MJ
authors.lastname: Dar
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Sandip B
authors.initials: SB
authors.lastname: Bharate
authors.affiliation: Department of Biochemistry, University of Kashmir, Srinagar, 190006, India.
authors.forename: Mohmmad Afzal
authors.initials: MA
authors.lastname: Zargar
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Qazi Naveed
authors.initials: QN
authors.lastname: Ahmed
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India. Electronic address: ahdar@iiim.ac.in.
authors.forename: Abid
authors.initials: A
authors.lastname: Hamid
mesh_terms: D000818:Animals; D048708:Cell Growth Processes; D002465:Cell Movement / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D045325:HCT116 Cells; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*
chemical_list: D009281:Naphthalenes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D052999:Quinazolinones
keywords: Angiogenesis; Lipogenesis; PI3K signaling; Quinazolinone; Warburg effect