Analysis of cellular sensitization with cisplatin-induced apoptosis by glucose-starved stress in cisplatin-sensitive and -resistant A431 cell line.
BACKGROUND
Most solid tumors show resistance to current chemotherapy. This drug resistance can be associated with stress conditions, such as glucose starvation, low pH and hypoxia. These conditions are not observed in normal tissues. These tumor specific conditions commonly cause the glucose-regulated stress response of cancer cells. This stress response leads to induction of resistance to multiple anticancer drugs, such as etoposide, doxorubicin, camptothecin and vincristine. An examination was made of the effect of the glucose-regulated protein (GRP)-inducing conditions on cellular sensitivity to cisplatin (CDDP), which is a widely used drug against solid tumors.


METHODS
We used CDDP resistant subline A431/CDDP2 from human epidermoid carcinoma cell line A431 as previously established. Glucose-starved response showed GRP78 protein by Western blotting. We generated the glucose-starved condition by exposing cells to 2-deoxyglucose (2-DG) and examined cellular sensitivity to CDDP. We next examined CDDP induced apoptosis in glucose-starved condition. Furthermore, we determined the JNK1/SAPK and caspase-3 protein levels by Western blotting.


RESULTS
The glucose-starved condition was up-regulate GRP78 in the parent A431 cell (A431/P). On the other hand, in A431/CDDP2, GRP78 levels were not changed. The GRP78 inducing stress condition led to cellular sensitization to CDDP in A431/P cells only. DNA fragmentation of A431/P treated with 2-DG increased CDDP-induced apoptosis. A431/CDDP2 was not different with CDDP induced apoptosis in glucose-starved stress condition. The reduction of CDDP-induced apoptosis under glucose-starved stress condition was influenced by JNK1/SAPK and caspase-3 proteins.


CONCLUSIONS
These results indicated that the glucose-starved stress condition was associated with increased sensitivity to CDDP in the up-regulated GRP78 cells. Furthermore, the reduction of CDDP-induced apoptosis can be considered as one of the CDDP resistant mechanisms in a glucose-starvation condition.
Mese
H
H
Department of Oral and Maxillofacial Surgery II, Okayama University Dental School, 2-5-1 Shikata-Cho, Okayama 700-8525, Japan. hmese@dent.okayama-u.ac.jp
Sasaki
A
A
Nakayama
S
S
Yokoyama
S
S
Sawada
S
S
Ishikawa
T
T
Matsumura
T
T
D000963:Antimetabolites / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000378:metabolism* / Q000494:pharmacology; D003470:Culture Media; D003847:Deoxyglucose / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D005947:Glucose / Q000502:physiology*; D006360:Heat-Shock Proteins; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*
D000963:Antimetabolites; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D003470:Culture Media; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D003847:Deoxyglucose; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D005947:Glucose; D002945:Cisplatin