PI3K-AKT Pathway Modulation by Thymoquinone Limits Tumor Growth and Glycolytic Metabolism in Colorectal Cancer.

Shahid Karim,Nasir Ali Siddiqui,Aftab Ahmad,Walaa A Abualsunun,Priyanka Sharma,Gamal A Gabr,Ibrahim M Ibrahim,Abdulhadi S Burzangi

doi:10.3390/ijms23042305

Abstract

Colorectal cancer (CRC) is the third leading cause of death in men and the fourth in women worldwide and is characterized by deranged cellular energetics. Thymoquinone, an active component from Nigella sativa, has been extensively studied against cancer, however, its role in affecting deregulated cancer metabolism is largely unknown. Further, the phosphoinositide 3-kinase (PI3K) pathway is one of the most activated pathways in cancer and its activation is central to most deregulated metabolic pathways for supporting the anabolic needs of growing cancer cells. Herein, we provide evidence that thymoquinone inhibits glycolytic metabolism (Warburg effect) in colorectal cancer cell lines. Further, we show that such an abrogation of deranged cell metabolism was due, at least in part, to the inhibition of the rate-limiting glycolytic enzyme, Hexokinase 2 (HK2), via modulating the PI3/AKT axis. While overexpression of HK2 showed that it is essential for fueling glycolytic metabolism as well as sustaining tumorigenicity, its pharmacologic and/or genetic inhibition led to a reduction in the observed effects. The results decipher HK2 mediated inhibitory effects of thymoquinone in modulating its glycolytic metabolism and antitumor effects. In conclusion, we provide evidence of metabolic perturbation by thymoquinone in CRC cells, highlighting its potential to be used/repurposed as an antimetabolite drug, though the latter needs further validation utilizing other suitable cell and/or preclinical animal models.

Highlights

IntroductionTumor cells are supported by metabolic rewiring in their growth, proliferation, survival, maintenance and reprogram the pathways of nutrient acquisition to meet the bioenergetics [1]
We report for the first time that TQ inhibits Hexokinase 2 (HK2)-mediated glycolytic metabolism, otherwise necessary to fuel the proliferation, clonogenicity and metastatic predisposition of Colorectal cancer (CRC) cells
phosphoinositide 3-kinase (PI3K)-AKT activation (Figure 3B), suggesting that TQ inhibits HK2 via modulating the PI3K-AKT pathway. To confirm whether such reduction in HK2 was PI3K-AKT-dependent, we used the selective pharmacologic inhibitor (LY294002) of PI3K and we observed a significant reduction in HK2 levels concomitant to PI3K-AKT inhibition (Figure 3C). These results demonstrate that TQ inhibits glycolytic metabolism in CRC cells by inhibiting HK2 via the PI3K-AKT pathway

Summary

Introduction

Tumor cells are supported by metabolic rewiring in their growth, proliferation, survival, maintenance and reprogram the pathways of nutrient acquisition to meet the bioenergetics [1]. This metabolic reprogramming is known as one of the prominent hallmarks of almost all cancers [2]. Many tumor cells reside in nutrient and oxygen-deficient environments, which makes a heterogeneous build-up that led cancer cells to adopt several methods to sustain mitochondrial function for survival [4]. Cells that proliferate at faster rates whether tumor cells or normal embryonic, immune and regenerating cells need ATP as well as anabolic constructive material for biomass improvement and nutrient refilling [5,6]

Methods

Results

Conclusion