A Comparison of Doxorubicin-Resistant Colon Cancer LoVo and Leukemia HL60 Cells: Common Features, Different Underlying Mechanisms

Abstract

Chemoresistance causes cancer relapse and metastasis, thus remaining the major obstacle to cancer therapy. While some light has been shed on the underlying mechanisms, it is clear that chemoresistance is a multifaceted problem strictly interconnected with the high heterogeneity of neoplastic cells. We utilized two different human cell lines, i.e., LoVo colon cancer and promyelocytic leukemia HL60 cells sensitive and resistant to doxorubicin (DXR), largely used as a chemotherapeutic and frequently leading to chemoresistance. LoVo and HL60 resistant cells accumulate less reactive oxygen species by differently modulating the levels of some pro- and antioxidant proteins. Moreover, the content of intracellular magnesium, known to contribute to protect cells from oxidative stress, is increased in DXR-resistant LoVo through the upregulation of MagT1 and in DXR-resistant HL60 because of the overexpression of TRPM7. In addition, while no major differences in mitochondrial mass are observed in resistant HL60 and LoVo cells, fragmented mitochondria due to increased fission and decreased fusion are detected only in resistant LoVo cells. We conclude that DXR-resistant cells evolve adaptive mechanisms to survive DXR cytotoxicity by activating different molecular pathways.

The Interplay between TRPM7 and MagT1 in Maintaining Endothelial Magnesium Homeostasis

“…Moreover, TRPM7-silencing HUVEC produce less ROS than controls, and this is associated with a decrease in the pro-oxidant TXNIP. A similar behavior coupling reduced TXNIP levels and decreased ROS was reported in LoVo cells resistant to doxorubicin [ 29 ]. On the contrary, oxidative stress generated by culturing HUVEC in Mg-deficient media or by exposing them to H 2 O 2 or high concentrations of D-glucose upregulates TRPM7 [ 6 , 12 ].…”

“…The inverse relation between TRPM7 and MagT1 has been reported in different cell types. Colon cancer LoVo cells show high levels of TRPM7 and low amounts of MagT1, while the opposite is true in their doxorubicin-resistant counterpart [ 29 ]. In differentiated murine C2C12 myoblasts, TRPM7 levels are reduced and MagT1 levels are increased when compared to undifferentiated cells [ 30 ].…”

Mitochondrial fusion–fission dynamics and its involvement in colorectal cancer

“…Chemoresistance presents a major challenge in cancer treatment. Research has established that doxorubicin‐ or oxaliplatin‐resistant colon cancer cells exhibit pronounced mitochondrial fragmentation due to increased division [ 40 , 45 ]. Although studies on mitochondrial morphology in the context of drug resistance in CRC stem cells (CCSCs) are lacking, the elevated mitophagy rate implies that mitochondrial fission is a mechanism underlying chemotherapy resistance in CCSCs [ 46 ].…”

Análisis transcriptómico del remodelado de la homeostasis del calcio intracelular en cáncer de colon

“…Por el contrario, otros estudios revelan que la expresión de TRPM7 es menor en CCR respecto del tejido normal (Ibrahim et al (2019)). Además, al igual que TRPM6, TRPM7 también presenta unos bajos niveles de expresión en células LoVo resistentes a doxorubicina lo que explicaría la superior tasa proliferativa respecto de las células sensibles a dicho tratamiento (Castiglioni et al (2015), Locatelli et al (2021)). Cabe destacar que las discrepancias entre los diferentes estudios podrían deberse a diferentes patrones de expresión de transportadores de Mg 2+ (Fioro Pla and Gkika (2013)).…”

“…También se ha detectado la alteración en la expresión de TRPM8, cuya localización celular aberrante se ha relacionado con la progresión tumoral (Monteith et al (2007), Bidaux et al (2007)). En cuanto a los tratamientos anticancerígenos, la reducción de TRPM6-7 favorece la resistencia a quimioterápicos como doxorrubicina (Castiglioni et al (2015), Locatelli et al (2021)). En este sentido, la infraexpresión del NCLX podría jugar también un papel clave en la quimiorresistencia (Pathak et al (2020)).…”