Dissection the mechanism(s) of folate deficiency-induced increases of drug and radiotherapy resistance acquisitions and metastatic propensity of SK-Hep-1 cells

Autor: Chun-Te Ho, 何俊德
Rok vydání: 2009
Druh dokumentu: 學位論文 ; thesis
Popis: 97
Our group recently found that a poorly-differentiated HCC, SK-Hep-1, could evade folate deficiency-induced apoptosis. However, the underlying mechanism associated with this hitherto unreported phenomenon is thus far elusive. Since we noted that Hep-G2 cells grown under folate deficient condition could elicit an accumulation of cytosolic and mitochondrial calcium (Ca2+) levels. This implied that homocysteine (Hcy)-induced ROS production could serve as a signal to modulate ER Ca2+ homeostasis leading ER stress and unfolded protein response (UPR). The activation of the UPR may lead to cell survival pathway by triggering the synthesis of ER chaperon proteins such as GRP-78 (also referred to as Bip). In this study, we present evidence to substantiate that SK-Hep-1 cultivated under folate deficient condition can engender drug resistance acquisition to anti-cancer drugs including cisplatin, taxol, doxorubicin and curcumin and radio-resistance acquisition (a fractionation dose of 3 × 7Gy). This phenomenon implied that folate deficient condition may be able to activate a survival pathway rendering cells resistant to these drugs and radiotherapy. Using western blotting technique, we demonstrated that sustained low levels of Hcy-induced ROS accumulation could result in a drastic increment of ER chaperon GRP-78 and phosphate-AKT expression which correlate in parallel with the induction of the drug resistance and radio-resistance acquisition. Taken together, this study provides the first evidence that folate deficiency can induce drug resistance and radio-resistance acquisition and Hcy-mediated expression of GRP-78 which may confer a protective pathway underlied this phenomenon.
Databáze: Networked Digital Library of Theses & Dissertations
Externí odkaz: