Antimicrobial peptaibols, novel suppressors of tumor cells, targeted calcium-mediated apoptosis and autophagy in human hepatocellular carcinoma cells.
BACKGROUND
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world which is highly chemoresistant to currently available chemotherapeutic agents. Thus, novel therapeutic targets are needed to be sought for the successful treatment of HCC. Peptaibols, a family of peptides synthesized non-ribosomally by the Trichoderma species and other fungi, exhibit antibiotic activities against bacteria and fungi. Few studies recently showed that peptaibols exerted cytotoxicity toward human lung epithelial and breast carcinoma cells. However, the mechanism involved in peptaibol-induced cell death remains poorly understood.


RESULTS
Here, we showed that Trichokonin VI (TK VI), a peptaibol from Trichoderma pseudokoningii SMF2, induced growth inhibition of HCC cells in a dose-dependent manner. It did not obviously impair the viability of normal liver cells at lower concentration. Moreover, the suppression of cell viability resulted from the programmed cell death (PCD) with characteristics of apoptosis and autophagy. An influx of Ca2+ triggered the activation of mu-calpain and proceeded to the translocation of Bax to mitochondria and subsequent promotion of apoptosis. On the other hand, typically morphological characteristics consistent with autophagy were also observed by punctate distribution of MDC staining and the induction of LC3-II, including extensive autophagic vacuolization and enclosure of cell organelles by these autophagosomes. More significantly, specific depletion of Bak expression by small RNA interfering (siRNA) could partly attenuate TK VI-induced autophagy. However, siRNA against Bax led to increased autophagy.


CONCLUSIONS
Taken together, these findings showed for the first time that peptaibols were novel regulators involved in both apoptosis and autophagy, suggesting that the class of peptaibols might serve as potential suppressors of tumor cells.
Shi
Mei
M
State Key Lab of Microbial Technology, Shandong University, Jinan, PR China.
Wang
Hong-Na
HN
Xie
Shu-Tao
ST
Luo
Yan
Y
Sun
Cai-Yun
CY
Chen
Xiu-Lan
XL
Zhang
Yu-Zhong
YZ
D000408:Alamethicin / Q000031:analogs & derivatives / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D008954:Models, Biological; D054848:Peptaibols / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D013997:Time Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D000890:Anti-Infective Agents; D054848:Peptaibols; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D000408:Alamethicin; C092827:trichokonin VI; D002154:Calpain; D002118:Calcium