Late-stage inhibition of autophagy enhances calreticulin surface exposure.
Calreticulin (CRT) exposure on the cell surface is essential for inducing immunogenic cell death by chemotherapy. Recent studies have shown conflicting effects of chemotherapy-induced autophagy on CRT exposure in cancer cells. Our data revealed that surface-exposed CRT (Ecto-CRT) emission was attenuated by inhibition of autophagy at early stages; however, inhibition of autophagy at late stages resulted in increased Ecto-CRT. Furthermore, neither autophagy activation nor endoplasmic reticulum (ER) stress induction alone was sufficient for CRT surface exposure. Moreover, chemotherapeutic agents that only activated autophagy without inducing ER stress could not increase Ecto-CRT; therefore, combined use of an autophagy activator and ER stress inducer could effectively promote CRT translocation to the plasma membrane. Together, our results highlight the potential of the combined use of ER stress inducers and autophagy late-stage inhibitors to reestablish and strengthen both the CRT exposure and immunogenicity of chemotherapeutic agents induced death cells.
Biotherapy Center, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Dan-Dan
DD
Li
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
Bo
B
Xie
Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Xiao-Jun
XJ
Wu
Biotherapy Center, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Jing-Jing
JJ
Li
Biotherapy Center, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Ya
Y
Ding
Biotherapy Center, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Xi-Zhi
XZ
Wen
Biotherapy Center, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Xing
X
Zhang
Department of Hepatic Surgery, Liver Transplant Center, Third Affiliated Hospital of Sun Yat-Sen University, TianHe District, Guangzhou 510630, China.|Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
Shu-Guang
SG
Zhu
Department of Hepatic Surgery, Liver Transplant Center, Third Affiliated Hospital of Sun Yat-Sen University, TianHe District, Guangzhou 510630, China.|Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
Wei
W
Liu
Biotherapy Center, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Xiao-Shi
XS
Zhang
Biotherapy Center, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Rui-Qing
RQ
Peng
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D000071189:Autophagy-Related Protein-1 Homolog / Q000235:genetics / Q000378:metabolism; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000077146:Irinotecan; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010766:Phosphorylation; D021381:Protein Transport; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
C491997:BECN1 protein, human; D000071186:Beclin-1; C576483:CALR protein, human; D037282:Calreticulin; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; C546842:MTOR protein, human; D000071189:Autophagy-Related Protein-1 Homolog; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D005472:Fluorouracil; D002166:Camptothecin
autophagy; calreticulin; chemotherapy induced immunogenic cell death; endoplasmic reticulum stress; mTOR