TY - JOUR

T1 - Prevention of High Glucose-Mediated EMT by Inhibition of Hsp70 Chaperone

AU - Никотина, Алина Дмитриевна

AU - Владимирова, Снежана Александровна

AU - Комарова, Елена Юрьевна

AU - Алексеев, Дмитрий Александрович

AU - Ефремов, Сергей Михайлович

AU - Леонова, Елизавета Андреевна

AU - Павлов, Ростислав Владимирович

AU - Карцев, Виктор

AU - Полоник, Cергей

AU - Маргулис, Борис Александрович

AU - Гужова, Ирина Владимировна

N1 - Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/6/27

Y1 - 2021/6/27

N2 - 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.

AB - 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.

KW - CL-43

KW - Colon cancer

KW - EMT

KW - Hsp70

KW - Hyperglycemia

KW - PES

KW - Humans

KW - Cell Transformation, Neoplastic/genetics

KW - HSP70 Heat-Shock Proteins/metabolism

KW - Blood Glucose

KW - Snail Family Transcription Factors/metabolism

KW - Hyperglycemia/etiology

KW - Cadherins/metabolism

KW - Biomarkers

KW - Cell Line, Tumor

KW - Epithelial-Mesenchymal Transition/drug effects

KW - Protein Binding

KW - Glucose/metabolism

KW - HEAT-SHOCK-PROTEIN-70

KW - APOPTOSIS

KW - ACTIVATION

KW - INVASIVENESS

KW - hyperglycemia

KW - INVASION

KW - PATHWAY

KW - CANCER METASTASIS

KW - colon cancer

KW - MESENCHYMAL TRANSITION

KW - SHOCK

KW - CARCINOMA

UR - http://www.scopus.com/inward/record.url?scp=85108655813&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/1fa97c50-dc63-367b-8427-e90e38abc11a/

U2 - 10.3390/ijms22136902

DO - 10.3390/ijms22136902

M3 - Article

C2 - 34199046

VL - 22

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 13

M1 - 6902

ER -