Modulation of effector caspase cleavage determines response of breast and lung tumor cell lines to chemotherapy.
In spite of compelling evidence-implicating caspases in drug-induced apoptosis, how tumors modulate caspase expression and activity to overcome the cytotoxicity of anticancer agents is not fully understood. To address this issue, we investigated the role of caspases-3 and caspase-7 in determining the response of breast and lung tumor cell lines to chemotherapy. We found that an early and late apoptotic response correlated with weak and strong cellular caspase-activation, respectively. The results highlight an underappreciated relationship of temporal apoptotic response with caspase-activation and drug resistance. Moreover, the extent of tumor growth restoration after drug withdrawal was dependent on the degree of endogenous blockage of caspase-3 and caspase-7 cleavages. This points to an unrecognized role of caspase modulation in tumor recurrence and suggests that targeting caspase cleavage is a rational approach to increasing potency of cancer drugs.
Odonkor
Charles A
CA
Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA.
Achilefu
Samuel
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism*; D053179:Caspase 7 / Q000378:metabolism*; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D017239:Paclitaxel