Two high-rate pentose-phosphate pathways in cancer cells.

Area of Science:

• Biochemistry
• Cancer Biology
• Cell Metabolism

Background:

• The pentose phosphate pathway (PPP) is crucial for cancer metabolic reprogramming.
• Glucose-6-phosphate dehydrogenase (G6PD) is the traditionally studied enzyme in the cytosolic PPP.
• Emerging evidence points to a less-characterized PPP involving hexose-6-phosphate dehydrogenase (H6PD) in the endoplasmic reticulum (ER).

Purpose of the Study:

• To investigate the biological role of H6PD in breast and lung cancer.
• To compare the functional impact of H6PD with the well-established G6PD in cancer cells.
• To elucidate the contribution of the ER-localized PPP to cancer cell biology.

Main Methods:

• Gene silencing of H6PD and G6PD in cancer cell lines.
• Quantification of PPP intermediates and D-ribose.
• Measurement of NADPH levels and cellular oxidative status.
• Assessment of cell proliferation rates.

Main Results:

• H6PD gene silencing significantly decreased PPP intermediates and D-ribose, comparable to G6PD silencing.
• Both H6PD and G6PD silencing led to reduced NADPH content and increased oxidative stress.
• Cell proliferation was similarly impaired by silencing either G6PD or H6PD.
• No cross-interference was observed between G6PD and H6PD expression.

Conclusions:

• The cancer PPP comprises both cytosolic (G6PD) and ER-localized (H6PD) pathways.
• H6PD plays a significant, previously underestimated role in cancer cell metabolism and proliferation.
• Understanding the ER-localized PPP is essential for a comprehensive view of its role in cancer biology.