Pachymic acid inhibits growth and induces apoptosis of pancreatic cancer in vitro and in vivo by targeting ER stress.
Pachymic acid (PA) is a purified triterpene extracted from medicinal fungus Poria cocos. In this paper, we investigated the anticancer effect of PA on human chemotherapy resistant pancreatic cancer. PA triggered apoptosis in gemcitabine-resistant pancreatic cancer cells PANC-1 and MIA PaCa-2. Comparative gene expression array analysis demonstrated that endoplasmic reticulum (ER) stress was induced by PA through activation of heat shock response and unfolded protein response related genes. Induced ER stress was confirmed by increasing expression of XBP-1s, ATF4, Hsp70, CHOP and phospho-eIF2α. Moreover, ER stress inhibitor tauroursodeoxycholic acid (TUDCA) blocked PA induced apoptosis. In addition, 25 mg kg-1 of PA significantly suppressed MIA PaCa-2 tumor growth in vivo without toxicity, which correlated with induction of apoptosis and expression of ER stress related proteins in tumor tissues. Taken together, growth inhibition and induction of apoptosis by PA in gemcitabine-resistant pancreatic cancer cells were associated with ER stress activation both in vitro and in vivo. PA may be potentially exploited for the use in treatment of chemotherapy resistant pancreatic cancer.
Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America.
Shujie
S
Cheng
Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America.
Kristen
K
Swanson
Amitabha Medical Clinic and Healing Center, Santa Rosa, California, United States of America.
Isaac
I
Eliaz
Departments of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, Indiana, United States of America.
Jeanette N
JN
McClintick
Departments of Pathology, School of Medicine, Indiana University, Indianapolis, Indiana, United States of America.
George E
GE
Sandusky
Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America; Departments of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, United States of America; DSTest Laboratories, Purdue Research Park, Indianapolis, Indiana, United States of America.
Daniel
D
Sliva
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055441:Poria / Q000737:chemistry*; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D056811:Unfolded Protein Response / Q000187:drug effects; D000071717:X-Box Binding Protein 1; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
C497109:ATF4 protein, human; D000970:Antineoplastic Agents; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D018840:HSP70 Heat-Shock Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014315:Triterpenes; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D003841:Deoxycytidine; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C102487:pachymic acid; D000093542:Gemcitabine