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Abstract
Hyperglycemia may contribute to the progression of carcinomas by triggering epithelial-to-mesenchymal transition (EMT). Some proteostasis systems are involved in metastasis; in this paper, we sought to explore the mechanism of Hsp70 chaperone in EMT. We showed that knockdown of Hsp70 reduced cell migration capacity concomitantly with levels of mRNA of the Slug, Snail, and Twist markers of EMT, in colon cancer cells incubated in high glucose medium. Conversely, treatment of cells with Hsp70 inducer U-133 were found to elevate cell motility, along with the other EMT markers. To prove that inhibiting Hsp70 may reduce EMT efficiency, we treated cells with a CL-43 inhibitor of the HSF1 transcription factor, which lowered Hsp70 and HSF1 content in the control and induced EMT in carcinoma cells. Importantly, CL-43 reduced migration capacity, EMT-linked transcription factors, and increased content of epithelial marker E-cadherin in colon cancer cells of three lines, including one derived from a clinical sample. To prove that Hsp70 chaperone should be targeted when inhibiting the EMT pathway, we treated cancer cells with 2-phenylethynesulfonamide (PES) and demonstrated that the compound inhibited substrate-binding capacity of Hsp70. Furthermore, PES suppressed EMT features, cell motility, and expression of specific transcription factors. In conclusion, the Hsp70 chaperone machine efficiently protects mechanisms of the EMT, and the safe inhibitors of the chaperone are needed to hamper metastasis at its initial stage.
Highlights
To test whether Hsp70 affects the motility of colon cancer cells, we used DLD1 cells with downregulated Hsp70 and those treated with U-133, a compound previously found to induce the heat shock response [24,25]
In the presence of a high content of glucose, DLD1scr cells started to move through the pores at 3–4 h after the recording was started, and in the end, the cell index was equal to 3.3 (Figure 1c) that nicely correlated with the wound closure assay where the healing reached 84.3 ± 2.0% (Figure 1d,e)
epithelialto-mesenchymal transition (EMT) is a multiphasic process leading to an expansion of phenotypically altered tumor cells with elevated resistance to anti-cancer drugs and increased motility as the necessary properties of metastasizing tissue
Summary
Colorectal cancer is currently the third most common cancer worldwide and the second most fatal one [1,2]. The extremely high mortality of patients with this type of cancer is due to the increased metastatic activity of cancer cells [3], associated with their phenotypic conversion, known as epithelial-to-mesenchymal transition (EMT) [4]. During this process, epithelial cells activate a program to remodel their organization and achieve a mesenchymal fate. Hyperglycemia is just one factor that contributes to the various types of oncological pathologies, including colorectal cancer, which is usually linked to diabetes.
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