Mitochondrial membrane potential (delta psi(mt)) in the coordination of p53-independent proliferation and apoptosis pathways in human colonic carcinoma cells.
We have previously defined depressed mitochondrial function as a determinant in colon cancer risk and progression and established that metabolism of butyrate, a short-chain fatty acid generated during the fermentation of fiber by endogenous intestinal bacteria, induces mitochondrial function-dependent growth arrest and apoptosis of colonic carcinoma cells in vitro. Here, we dissect the relationships among mitochondrial function, growth arrest, and apoptosis, reporting that initiation and maintenance of butyrate-mediated p53-independent p21WAF1/Cip1 induction and subsequent G0/G1 arrest require an intact mitochondrial membrane potential (delta psi(mt)) and that the process of dissipation of the delta psi(mt) is then essential for initiation of a butyrate-induced apoptotic cascade. Thus, we hypothesize that mitochondria play a pivotal role in coordinating proliferation and apoptosis pathways, a coordination that must be tightly regulated in rapidly renewing tissues, such as the colonic mucosa.
Heerdt
B G
BG
Albert Einstein Cancer Center, Bronx, New York 10467, USA.
Houston
M A
MA
Anthony
G M
GM
Augenlicht
L H
LH
D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002449:Cell Aggregation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003110:Colonic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology; D003574:Cytochrome c Group / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007399:Interphase / Q000187:drug effects; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012402:Rotenone / Q000494:pharmacology; D013804:Thenoyltrifluoroacetone / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014475:Uncoupling Agents / Q000494:pharmacology
D002087:Butyrates; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003574:Cytochrome c Group; D014475:Uncoupling Agents; D012402:Rotenone; D020148:Butyric Acid; D013804:Thenoyltrifluoroacetone