Posted: May 15th, 2023

Glycolysis, Warburg effect & Cancer: Role of thiols?

Topic 250 WORDS: Glycolysis, Warburg effect & Cancer: Role of thiols?

This week you learned about glycolysis and the chemical reactions and enzymes involved in this important metabolic pathway. You further learned that glyceraldehyde phosphate dehydrogenase (GAPDH) enzyme is not only an important key regulatory enzyme of glycolysis, but also recognized as a “moonshining” enzyme. GAPDH is also long known as an enzyme that is prone to inhibition by many toxins, e.g., Pertussis toxin, alkylating agents and many thiol compounds. You also heard about the Warburg effect in connection with glycolysis.

As you work on this week’s discussion board assignment, consider the following:

Cervical cancer is the second highest number of deaths in female cancers, exceeded only by breast cancer. This cancer carries high risks of morbidity and mortality amongst women.
Most cervical cancers cells show abnormally high glycolysis rates.
The current standard of care for locally advanced cervical cancer is concurrent cisplatin chemotherapy with pelvic irradiation.
Despite significant advances in radiation treatment delivery, more than 30% of patients fail this treatment.
This week:

Please read this scientific article: Rashmi R., Huang X. et al. Radio-resistant cervical cancers are sensitive to inhibition of glycolysis and redox metabolism. Cancer Res. 2018 March 15; 78(6): 1392–1403.
Do some research on NCBI Pubmed (www.ncbi.nlm.nih.gov/pubmed) on this week’s topic.
Then discuss the following aspects with your classmates:
What is the Warburg effect? How is it connected to glycolysis?
What are some of the reported metabolic characteristics of cervical cancer cells?
What do scientists consider important thiols which may be responsible for the resistance of cervical cancer cells to radio and brachytherapy?
Why and how do increased thiol levels confer increased resistance to radio- and brachytherapy? And how can thiol levels be manipulated?
Which glycolysis enzyme is the most likely target candidate for thiol therapy? Why?

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The Warburg effect refers to the observation that cancer cells have an altered metabolic phenotype characterized by a preference for glycolysis, even in the presence of oxygen (aerobic glycolysis). Normally, cells generate energy through aerobic respiration, which involves the breakdown of glucose in the presence of oxygen to produce carbon dioxide, water, and a large amount of ATP. However, cancer cells exhibit increased glucose uptake and rely heavily on glycolysis, which converts glucose into lactate, even in the presence of sufficient oxygen. This shift towards glycolysis is thought to provide several advantages to cancer cells, including rapid ATP production and the diversion of metabolic intermediates for biosynthesis to support their proliferative growth.

Cervical cancer cells also exhibit enhanced glycolytic activity, similar to other cancer cells. They have increased glucose uptake and lactate production, indicating an upregulated glycolytic pathway. Furthermore, cervical cancer cells have been reported to exhibit alterations in various metabolic pathways, including increased glutamine metabolism, altered lipid metabolism, and increased production of reactive oxygen species (ROS).

Thiols are a class of compounds that contain a sulfhydryl (-SH) group, such as glutathione (GSH). Scientists have identified thiols as important factors contributing to the radio- and brachytherapy resistance observed in cervical cancer cells. These thiols act as antioxidants and help neutralize ROS, which are generated during radiation therapy. Increased levels of thiols in cancer cells can reduce the effectiveness of radiotherapy by scavenging ROS and protecting cancer cells from DNA damage and cell death.

To overcome thiol-mediated resistance, researchers have explored strategies to manipulate thiol levels in cancer cells. One approach is to target the enzymes involved in thiol synthesis or utilization pathways. Glutathione synthesis inhibitors, such as buthionine sulfoximine (BSO), have been studied to reduce thiol levels and sensitize cancer cells to radiation therapy.

Among the glycolysis enzymes, glyceraldehyde phosphate dehydrogenase (GAPDH) is a potential target for thiol therapy. GAPDH is not only involved in the glycolytic pathway but is also susceptible to inhibition by thiols. By targeting GAPDH and inhibiting its activity, it may be possible to disrupt glycolysis and sensitize cancer cells to radiation therapy.

The Warburg effect describes the metabolic shift towards glycolysis in cancer cells. Cervical cancer cells exhibit high glycolytic rates and altered metabolism. Thiols, such as glutathione, play a role in radiotherapy resistance by protecting cancer cells from ROS-induced damage. Manipulating thiol levels, particularly by targeting GAPDH, may offer a potential therapeutic approach to enhance the effectiveness of radio- and brachytherapy in cervical cancer treatment.