Interplay between cell cycle and autophagy induced by boswellic acid analog

Anup S. Pathania, Santosh K. Guru, Suresh Kumar, Ashok Kumar, Masroor Ahmad, Shashi Bhushan, Parduman R. Sharma, Priya Mahajan, Bhahwal A. Shah, Simmi Sharma, Amit Nargotra, Ram Vishwakarma, Hasan Korkaya, Fayaz Malik

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12 Scopus citations

Abstract

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 (IC 50 1 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.

Original languageEnglish (US)
Article number33146
JournalScientific reports
Volume6
DOIs
StatePublished - Sep 29 2016

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    Pathania, A. S., Guru, S. K., Kumar, S., Kumar, A., Ahmad, M., Bhushan, S., Sharma, P. R., Mahajan, P., Shah, B. A., Sharma, S., Nargotra, A., Vishwakarma, R., Korkaya, H., & Malik, F. (2016). Interplay between cell cycle and autophagy induced by boswellic acid analog. Scientific reports, 6, [33146]. https://doi.org/10.1038/srep33146