Interplay between cell cycle and autophagy induced by boswellic acid analog.
In this study, we investigated the role of autophagy induced by boswellic acid analog BA145 on cell cycle progression in pancreatic cancer cells. BA145 induced robust autophagy in pancreatic cancer cell line PANC-1 and exhibited cell proliferation inhibition by inducing cells to undergo G2/M arrest. Inhibition of G2/M progression was associated with decreased expression of cyclin A, cyclin B, cyclin E, cdc2, cdc25c and CDK-1. Pre-treatment of cells with autophagy inhibitors or silencing the expression of key autophagy genes abrogated BA145 induced G2/M arrest and downregulation of cell cycle regulatory proteins. It was further observed that BA145 induced autophagy by targeting mTOR kinase (IC501 μM), leading to reduced expression of p-mTOR, p-p70S6K (T389), p-4EBP (T37/46) and p-S6 (S240/244). Notably, inhibition of mTOR signalling by BA145 was followed by attendant activation of AKT and its membrane translocation. Inhibition of Akt through pharmacological inhibitors or siRNAs enhanced BA145 mediated autophagy, G2/M arrest and reduced expression of G2/M regulators. Further studies revealed that BA145 arbitrated inhibition of mTOR led to the activation of Akt through IGFR/PI3k/Akt feedback loop. Intervention in IGFR/PI3k/Akt loop further depreciated Akt phosphorylation and its membrane translocation that culminates in augmented autophagy with concomitant G2/M arrest and cell death.
Departments of Cancer Pharmacology, Natural Products Microbes; Indian Institute of Integrative Medicine, Canal road Jammu, Jammu and Kashmir, 180001, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.
Anup S
AS
Pathania
Departments of Cancer Pharmacology, Natural Products Microbes; Indian Institute of Integrative Medicine, Canal road Jammu, Jammu and Kashmir, 180001, India.
Santosh K
SK
Guru
Departments of Cancer Pharmacology, Natural Products Microbes; Indian Institute of Integrative Medicine, Canal road Jammu, Jammu and Kashmir, 180001, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.
Suresh
S
Kumar
Departments of Cancer Pharmacology, Natural Products Microbes; Indian Institute of Integrative Medicine, Canal road Jammu, Jammu and Kashmir, 180001, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.
Ashok
A
Kumar
Departments of Cancer Pharmacology, Natural Products Microbes; Indian Institute of Integrative Medicine, Canal road Jammu, Jammu and Kashmir, 180001, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.
Masroor
M
Ahmad
Departments of Cancer Pharmacology, Natural Products Microbes; Indian Institute of Integrative Medicine, Canal road Jammu, Jammu and Kashmir, 180001, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.
Shashi
S
Bhushan
Departments of Cancer Pharmacology, Natural Products Microbes; Indian Institute of Integrative Medicine, Canal road Jammu, Jammu and Kashmir, 180001, India.
Parduman R
PR
Sharma
Discovery Informatics and Natural Products Microbes; Indian Institute of Integrative Medicine, Canal road Jammu, Jammu and Kashmir, 180001, India.
Priya
P
Mahajan
Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.|Natural Products Microbes; Indian Institute of Integrative Medicine, Canal road Jammu, Jammu and Kashmir, 180001, India.
Bhahwal A
BA
Shah
Natural Products Microbes; Indian Institute of Integrative Medicine, Canal road Jammu, Jammu and Kashmir, 180001, India.
Simmi
S
Sharma
Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.|Discovery Informatics and Natural Products Microbes; Indian Institute of Integrative Medicine, Canal road Jammu, Jammu and Kashmir, 180001, India.
Amit
A
Nargotra
Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.|Natural Products Microbes; Indian Institute of Integrative Medicine, Canal road Jammu, Jammu and Kashmir, 180001, India.
Ram
R
Vishwakarma
Department of Biochemistry and Molecular Biology, Georgia Regents University Cancer Centre, 1410 Laney Walker Boulevard CN2136, Augusta, GA, 30912, USA.
Hasan
H
Korkaya
Departments of Cancer Pharmacology, Natural Products Microbes; Indian Institute of Integrative Medicine, Canal road Jammu, Jammu and Kashmir, 180001, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.
Fayaz
F
Malik
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