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

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.

Antiproliferative effect of thymoquinone on human colon cancer cells: Is it dependent on glycolytic pathway?

“…In addition, researchers showed that glucose levels increased while lactate levels decreased in TQ-treated group (18). In another study, similar results were expressed by Karim et al (2022) in colorectal cancer cell lines (19). In the present study, lower glucose concentration is result of high consumption in control group.…”

Apoptotic Mechanisms of Quercetin in Liver Cancer: Recent Trends and Advancements

“…One of the most often over-activated intracellular pathways in a number of human malignancies is the PI3K/AKT pathway. This pathway leads to the development of cancer, tumor cell proliferation, invasion, and metastasis by acting on many downstream target proteins [ 57 ]. In a human hepatoma cell line, quercetin caused the PI-3-kinase/Akt and ERK pathways to be inhibited (HepG2).…”

The Role of Thymoquinone in Inflammatory Response in Chronic Diseases

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