TY - UNPB

T1 - Conditioned media from MCF7 and BT474 breast cancer cells induce insulin resistance in skeletal muscle myotubes

AU - Ali, Mona Sadek

AU - Han, Xiuqing

AU - Li, Jingwen

AU - Jäättelä, Marja

AU - Sylow, Lykke

N1 - bioRxiv preprint posted January 28, 2020.

PY - 2020/1/28

Y1 - 2020/1/28

N2 - Background: Metabolic disorders are prevalent in women with breast cancer and breast cancer survivors. Such disorders increase breast cancer mortality and likelihood of relapse 2- and 3-fold, respectively. However, there is a severe lack of research into the physiological sequelae of breast cancer, including the metabolic health consequences. The aim of the present study was to providenovel insights into the causes of metabolic disturbances associated with breast cancer by investigating the effects of breast cancer on insulin sensitivity in skeletal muscle. Method: L6 myotubes stably expressing GLUT4 were incubated for 72 hours in normal growth medium or medium supplemented with 25% conditioned media (CM) from either MCF7 or BT474 breast cancer cells. Basal and insulin- (100nM) stimulated GLUT4 translocation, 2-deoxyglucose (2DG) uptake, and intracellular insulin signaling was determined in day 7 myotubes.Results: Basal- and insulin-stimulated GLUT4 translocation was reduced in L6 myotubes incubated with MCF7 (basal: -7%, insulin: -14%, p<0.01) or BT474 (basal: -16%, insulin: -8%, p<0.01) breast cancer CM. Insulin-stimulated 2DG uptake in L6 myotubes was also reduced by MCF7 (-5%, p<0.05) and BT474 (-10%, p<0.05) breast cancer CM. Insulin-stimulated p-AktThr308 (but not pAktSer473) phosphorylation tended to be reduced (-25%, p<0.1) in L6 myotubes incubated with MCF7 or BT474 breast cancer CM, while p-TBC1D4Thr642 phosphorylation was enhanced (+34%, p<0.05) by MCF7 breast cancer CM.Conclusion: We conclude that breast cancer reduces muscle insulin responsiveness, evidenced as reduced insulin-stimulated GLUT4 translocation, downregulated glucose uptake, and blunted intracellular insulin sigaling in L6 myotubes incubated with breast cancer cell CM. Thus, skeletal muscle insulin resistance might contribute to metabolic disorders prevalent in women with breast cancer and could be a potential treatment target.

AB - Background: Metabolic disorders are prevalent in women with breast cancer and breast cancer survivors. Such disorders increase breast cancer mortality and likelihood of relapse 2- and 3-fold, respectively. However, there is a severe lack of research into the physiological sequelae of breast cancer, including the metabolic health consequences. The aim of the present study was to providenovel insights into the causes of metabolic disturbances associated with breast cancer by investigating the effects of breast cancer on insulin sensitivity in skeletal muscle. Method: L6 myotubes stably expressing GLUT4 were incubated for 72 hours in normal growth medium or medium supplemented with 25% conditioned media (CM) from either MCF7 or BT474 breast cancer cells. Basal and insulin- (100nM) stimulated GLUT4 translocation, 2-deoxyglucose (2DG) uptake, and intracellular insulin signaling was determined in day 7 myotubes.Results: Basal- and insulin-stimulated GLUT4 translocation was reduced in L6 myotubes incubated with MCF7 (basal: -7%, insulin: -14%, p<0.01) or BT474 (basal: -16%, insulin: -8%, p<0.01) breast cancer CM. Insulin-stimulated 2DG uptake in L6 myotubes was also reduced by MCF7 (-5%, p<0.05) and BT474 (-10%, p<0.05) breast cancer CM. Insulin-stimulated p-AktThr308 (but not pAktSer473) phosphorylation tended to be reduced (-25%, p<0.1) in L6 myotubes incubated with MCF7 or BT474 breast cancer CM, while p-TBC1D4Thr642 phosphorylation was enhanced (+34%, p<0.05) by MCF7 breast cancer CM.Conclusion: We conclude that breast cancer reduces muscle insulin responsiveness, evidenced as reduced insulin-stimulated GLUT4 translocation, downregulated glucose uptake, and blunted intracellular insulin sigaling in L6 myotubes incubated with breast cancer cell CM. Thus, skeletal muscle insulin resistance might contribute to metabolic disorders prevalent in women with breast cancer and could be a potential treatment target.

U2 - 10.1101/2020.01.27.921262

DO - 10.1101/2020.01.27.921262

M3 - Preprint

BT - Conditioned media from MCF7 and BT474 breast cancer cells induce insulin resistance in skeletal muscle myotubes

PB - bioRxiv

ER -