Orlistat Induced Endoplasmic Reticulum Stress Mediated Apoptosis and Protective Autophagy in PANC-1 Cells: The Key Role of JNK and Mitochondrial Dependent Signalling
Vishal Sharma1, Raja Ramachandran2, Samriti Dhawan3 and Jagdeep Kaur1*
1Department of Biotechnology, Panjab University, Chandigarh, India
2Post Graduate Institute of Medical Education and Research, Chandigarh, India
3Department of Biotechnology, Goswami Ganesh Dutta Sanatan Dharma College, Chandigarh, India
*Corresponding Author: Jagdeep Kaur, Department of Biotechnology, Panjab University, Chandigarh, India.
January 09, 2023; Published: June 27, 2023
Orlistat primarily designed to treat obesity is a lipase inhibitor, it is also reported to enhance apoptosis in Human Pancreatic Cancer Cells (PANC-1). Therefore efforts were made in the present investigation to evaluate the effect of orlistat on different parameters playing role in apoptosis and autophagy. Orlistat inhibited the PANC-1 cells growth in a dose-dependent manner with IC50 40 µM after 48 h. Treatment of PANC-1 with 10 µM and 20 µM orlistat for 48 h resulted in autophagy induction. Orlistat treatment of PANC-1 cells caused endoplasmic reticulum stress, as evidenced by increased cytosolic calcium levels, XBP1 splicing, GRP78, and CHOP up-regulation. Orlistat induced ROS generation and translocation of Bax from cytosol to mitochondrion with enhanced cytosolic cytochrome c level. Similarly, a simultaneously enhanced level of cytochrome c was found to be associated with caspase 3 activation and PARP cleavage. These observations suggested that orlistat induced endoplasmic reticulum stress, mitochondrion and ROS mediated cytotoxic action in PANC-1 cells. Further orlistat treatment reveals endoplasmic reticulum stress mediating autophagy through activation of the JNK pathway. To examine whether the autophagy induced by endoplasmic reticulum stress plays a role in cell survival or cell death, autophagy was blocked by 3-Methyladenine. Inhibition of orlistat induced autophagy using 3-Methyladenine results in enhanced apoptosis and suggested protective nature of orlistat induced autophagy in PANC-1. Collectively, all these studies suggested that orlistat had an anti-cancer effect on pancreatic cancer cells. In addition, autophagy played a pro-survival role, suppressing which the orlistat-induced anti-cancer effect would be more significant.
Keywords: Orlistat; Pancreatic Cancer; Autophagy; Endoplasmic Reticulum Stress; Apoptosis
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