Caffeic Acid Expands Anti-Tumor Effect of Metformin in Human Metastatic Cervical Carcinoma HTB-34 Cells: Implications of AMPK Activation and Impairment of Fatty Acids De Novo Biosynthesis.

Malgorzata Tyszka-Czochara,Marcin Majka,Pawel Konieczny

doi:10.3390/ijms18020462

Malgorzata Tyszka-Czochara, Marcin Majka + Show 1 more

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https://doi.org/10.3390/ijms18020462

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Abstract

The efficacy of cancer treatments is often limited and associated with substantial toxicity. Appropriate combination of drug targeting specific mechanisms may regulate metabolism of tumor cells to reduce cancer cell growth and to improve survival. Therefore, we investigated the effects of anti-diabetic drug Metformin (Met) and a natural compound caffeic acid (trans-3,4-dihydroxycinnamic acid, CA) alone and in combination to treat an aggressive metastatic human cervical HTB-34 (ATCC CRL1550) cancer cell line. CA at concentration of 100 µM, unlike Met at 10 mM, activated 5'-adenosine monophosphate-activated protein kinase (AMPK). What is more, CA contributed to the fueling of mitochondrial tricarboxylic acids (TCA) cycle with pyruvate by increasing Pyruvate Dehydrogenase Complex (PDH) activity, while Met promoted glucose catabolism to lactate. Met downregulated expression of enzymes of fatty acid de novo synthesis, such as ATP Citrate Lyase (ACLY), Fatty Acid Synthase (FAS), Fatty Acyl-CoA Elongase 6 (ELOVL6), and Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells. In conclusion, CA mediated reprogramming of glucose processing through TCA cycle via oxidative decarboxylation. The increased oxidative stress, as a result of CA treatment, sensitized cancer cells and, acting on cell biosynthesis and bioenergetics, made HTB-34 cells more susceptible to Met and successfully inhibited neoplastic cells. The combination of Metformin and caffeic acid to suppress cervical carcinoma cells by two independent mechanisms may provide a promising approach to cancer treatment.

Highlights

Despite the recent development of new anti-tumor therapies, cancer still remains one of the leading causes of death in humans
We focused on the effect of Met and CA on the regulatory proteins of FA de novo biosynthesis
We found that 100 μM treatment of CA for 24 h inhibited proliferation of cells compared with untreated control (p < 0.05 vs. control)

Summary

Introduction

Despite the recent development of new anti-tumor therapies, cancer still remains one of the leading causes of death in humans. The malignancy of the cervix is the second most common cancer in women world-wide [1]. The efficacy of conventional cancer treatment is often limited and associated with substantial toxicity affecting the whole organism. The urgent challenge of therapy is to limit metastasis of cancer cells in the body. This is extremely difficult due to metabolic advantages developed by tumors compared with normal tissues. The intensively proliferating cancer cells reprogram their metabolism to fulfill high metabolic requirements. The critical aspects of metabolic reprogramming in cancer cells substantially contribute to the Warburg effect, involving changes in the glycolytic pathway

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