Abstract
Short-chain fatty acids (SCFAs) are the major by-products of bacterial fermentation of undigested dietary fibers in the large intestine. SCFAs, mostly propionate and butyrate, inhibit proliferation and induce apoptosis in colon cancer cells, but clinical trials had mixed results regarding the anti-tumor activities of SCFAs. Herein we demonstrate that propionate and butyrate induced autophagy in human colon cancer cells to dampen apoptosis whereas inhibition of autophagy potentiated SCFA induced apoptosis. Colon cancer cells, after propionate treatment, exhibited extensive characteristics of autophagic proteolysis: increased LC3-I to LC3-II conversion, acidic vesicular organelle development, and reduced p62/SQSTM1 expression. Propionate-induced autophagy was associated with decreased mTOR activity and enhanced AMP kinase activity. The elevated AMPKα phosphorylation was associated with cellular ATP depletion and overproduction of reactive oxygen species due to mitochondrial dysfunction involving the induction of MPT and loss of Δψ. In this context, mitochondria biogenesis was initiated to recover cellular energy homeostasis. Importantly, when autophagy was prevented either pharmacologically (3-MA or chloroquine) or genetically (knockdown of ATG5 or ATG7), the colon cancer cells became sensitized toward propionate-induced apoptosis through activation of caspase-7 and caspase-3. The observations indicate that propionate-triggered autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death, whereas application of an autophagy inhibitor (Chloroquine) is expected to enhance the therapeutic efficacy of SCFAs in inducing colon tumor cell apoptosis.
Highlights
A number of antineoplastic therapies, including radiotherapy and DNA-damaging chemotherapy, have been observed to induce autophagy.[8,9] Whether autophagy induced by antineoplastic therapies facilitates tumor cell death or represents a self-defense mechanism for resisting therapy remains controversial
Autophagy serves as an adaptive response as cotreatment with autophagy inhibitors or expression of shRNA directed against ATG5/7 augmented propionate-induced cell death
Our data suggest that autophagy is an adaptive strategy allowing for augmented resistance to apoptotic stimuli triggered by SCFAs in colon cancer cells
Summary
A number of antineoplastic therapies, including radiotherapy and DNA-damaging chemotherapy, have been observed to induce autophagy.[8,9] Whether autophagy induced by antineoplastic therapies facilitates tumor cell death or represents a self-defense mechanism for resisting therapy remains controversial. Several observations support the argument that autophagy is detrimental to cancer cell survival, including the fact that the ability of radiation or chemotherapy to induce cell death in cancer cell lines that display resistance to apoptosis depends on autophagy induction.[8] On the other hand, mounting evidence suggests that autophagy represents a self-protective strategy against antineoplastic treatment by abrogating apoptosis.[10] These seemingly contradictory findings indicate that there is not a unique paradigm addressing the role of autophagy in tumorigenesis. Received 03.12.09; revised 18.6.10; accepted 05.7.10; Edited by M Piacentini; published online 08.10.10 autophagy and induction of autophagy attenuated the therapeutic efficacy of SCFAs toward colon cancer
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