Glucose controls cathepsin expression in Ras-transformed fibroblasts

Area of Science:

• Biochemistry
• Cell Biology
• Cancer Research

Background:

• Overexpression and altered trafficking of cathepsins are linked to tumor malignancy.
• Transformed cells exhibit metabolic deviations like aerobic glycolysis to adapt to nutrient conditions.
• The impact of altered cell metabolism on proteinase expression in malignancy is not well understood.

Purpose of the Study:

• To investigate whether altered cell metabolism influences the expression of proteinases involved in malignancy.
• To determine the effect of D-glucose on cathepsin activity and expression in transformed cells.

Main Methods:

• Utilized Kirsten-virus-transformed 3T3 fibroblasts (KBALB) and BALB/3T3 fibroblasts.
• Assessed cathepsin activity, mRNA levels, and protein forms.
• Investigated the role of D-glucose, D-mannose, and sugar analogues (D-galactose, L-glucose, 3-O-methyl-D-glucose).
• Employed stable transfection with constitutively activated Ras.

Main Results:

• D-glucose selectively increased active forms of cathepsins L, B, and D in KBALB cells.
• D-glucose enhanced mature forms of cathepsins B and L without altering mRNA levels or secretion.
• Induction required high cell density and was observed in Ras-transformed cells but not normal cells.
• D-mannose mimicked D-glucose effects, while non-metabolized sugars and a glucose analogue did not.

Conclusions:

• Transformed cells modulate active proteinase production, including cathepsins, in response to nutrient supply and altered metabolism.
• Metabolic reprogramming in cancer cells can directly impact the expression of enzymes crucial for malignant progression.
• Findings highlight a link between cellular metabolism and the enzymatic machinery driving cancer.