HtrA1 downregulation induces cisplatin resistance in lung adenocarcinoma by promoting cancer stem cell-like properties.

Cisplatin (CDDP) resistance usually develops during lung adenocarcinoma (LAC) therapy. However, the comprehensive mechanisms remain largely unclear. In this study, we first established a CDDP-resistant LAC cell line-A549/CDDP from its parental cell line-A549. The results showed that CDDP resistance in A549/CDDP cells correlates with acquirement of cancer stem cell-like properties (increased percentage of CD133-expressing subpopulation, sphere formation and levels of some pluripotency-associated markers). HtrA1 expression at both mRNA and protein levels was reduced in CDDP-resistant A549/CDDP cells compared with that in A549 cells. Ectopic expression of HtrA1 in A549/CDDP cells reversed cancer stem cell-like properties and CDDP resistance. In A549 cells, stable knockdown of HtrA1 expression promoted cancer stem cell-like properties and CDDP insensitivity, however, these effects were blocked by inhibition of PI3K/Akt pathway using LY294002. Furthermore, HtrA1 knockdown could significantly stimulate PI3K/Akt signaling in A549 cells. In vivo studies, HtrA1 knockdown promoted tumorigenesis and conferred CDDP resistance in xenograft A549 tumors, which were reversed by intraperitoneal injection of LY294002. In conclusion, these results indicate that HtrA1 downregulation confers CDDP resistance by inducing cancer stem cell-like properties via PI3K/Akt-dependent pathway in A549 cells. Therefore, HtrA1 may be a potential target for overcoming CDDP resistance in LAC.

Xu Y ，Jiang Z ，Zhang Z ，Sun N ，Zhang M ，Xie J ，Li T ，Hou Y ，Wu D ... -  《-》

Par-4 downregulation confers cisplatin resistance in pancreatic cancer cells via PI3K/Akt pathway-dependent EMT.

Cisplatin (CDDP) efficiency in pancreatic cancer therapy is limited due to development of drug resistance. However, the comprehensive mechanisms remain largely unclear. In this study, we first established a CDDP-resistant pancreatic cancer cell line-BXPC-3/CDDP from its parental cell line-BXPC-3. The results showed that CDDP resistance in BXPC-3/CDDP cells correlates with changes in cellular EMT phenotypes. Prostate apoptosis response-4 (Par-4) expression at both mRNA and protein levels were reduced in CDDP-resistant BXPC-3/CDDP cells compared with that in BXPC-3 cells. Ectopic expression of Par-4 reversed EMT and CDDP resistance in BXPC-3/CDDP cells. In BXPC-3 cells, knockdown of Par-4 expression induces EMT and CDDP insensitivity, however, these effects were blocked by inhibition of PI3K/Akt pathway using LY294002. Furthermore, Par-4 knockdown could significantly stimulate PI3K/Akt signaling in BXPC-3 cells. In vivo studies, xenograft BXPC-3 tumors were sensitive to CDDP treatment. Treatment with CDDP alone had little effect on the growth of Par-4 siRNA-transfected BXPC-3 tumors in nude mice and the survival rate compared with control. Inhibition of PI3K/Akt pathway using LY294002 reversed CDDP resistance in Par-4 siRNA-transfected BXPC-3 tumors. In conclusion, these results indicate that Par-4 downregulation confers CDDP resistance via PI3K/Akt pathway-dependent EMT in BXPC-3 cells. Therefore, Par-4 may be a potential target for overcoming CDDP resistance in pancreatic cancer.

Tan J ，You Y ，Xu T ，Yu P ，Wu D ，Deng H ，Zhang Y ，Bie P ... -  《-》

HtrA1 Down-regulation Induces Cisplatin Resistance in Colon Cancer by Increasing XIAP and Activating PI3K/Akt Pathway.

The high temperature requirement factor A1 (HtrA1), a member of serine protease family, has been reported to be down-regulated in various cancer types and correlate with chemoresistance. However, the function of HtrA1 in colon cancer remains unclear. This study investigated the role of HtrA1 in cisplatin (CDDP) resistance of colon cancer. We found that HtrA1 was up-regulated in colon cancer cell line SW480 incubated with CDDP. By treating SW480 cells to a continuous exposure to CDDP, we developed CDDP-resistant SW480/CDDP cells and found that the mRNA and protein levels of HtrA1 were reduced. Besides, the stable knock-down of HtrA1 in SW480 transfected with HtrA1 shRNA could also induce chemoresistance against CDDP. To the contrary, ectopic expression of HtrA1 in SW480/CDDP cells abrogated CDDP resistance. The mechanism underlying HtrA-1 down-regulation induced chemoresisance was also investigated. In SW480/CDDP cells and SW480 cells with HtrA1 knock-down, X-linked inhibitor of apoptosis protein (XIAP) was increased, while the interfering of XIAP impeded CDDP resistance in SW480/CDDP cells. We also found that Akt was activated in SW480/CDDP cells and SW480 cells with HtrA1 knock-down. The inhibition of Akt activation reversed CDDP resistance. In conclusion, our results indicate that HtrA1 down-regulation induces CDDP resistance in colon cancer by increasing XIAP and activating PI3K/Akt pathway. This study provides evidence that HtrA1 might be a therapeutic target for overcoming CDDP resistance in colon cancer.

Xiong Z ，Fu Z ，Shi J ，Jiang X ，Wan H ... -  《-》

Bisdemethoxycurcumin sensitizes cisplatin-resistant lung cancer cells to chemotherapy by inhibition of CA916798 and PI3K/AKT signaling.

Wang HJ ，Yang ZX ，Dai XT ，Chen YF ，Yang HP ，Zhou XD ... -  《-》

CNTN-1 Enhances Chemoresistance in Human Lung Adenocarcinoma Through Induction of Epithelial-Mesenchymal Transition by Targeting the PI3K/Akt Pathway.

Chemoresistance has been a major obstacle to the effective treatment of lung cancer. Previously, we found that contactin-1 (CNTN-1) is related to cisplatin resistance in lung adenocarcinoma. Here, we aimed to investigate the underlying mechanism behind the role of CNTN-1 in cisplatin resistance in lung adenocarcinoma. EMT-associated phenotypes, including alterations in cellular morphology and marker (E-cadherin, N-cadherin and Vimentin) expression, were compared between A549 cells and A549/DDP cells (a cisplatin-resistant cell line of lung adenocarcinoma with abnormal CNTN-1 expression) by using real-time time PCR and Western blotting. Other methods, including CNTN-1 overexpression in A549 cells and CNTN-1 knockdown in A549/DDP cells, were also used to investigate the role of CNTN-1 in mediating the EMT phenotype and thr resulting cisplatin resistance and malignant progression of cancer cells in vitro and in vivo. A549/DDP cells exhibited an EMT phenotype and aggravated malignant behaviors. CNTN-1 knockdown in A549/DDP cells partly reversed the EMT phenotype, increased drug sensitivity, and attenuated the malignant progression whereas CNTN-1 overexpression in A549 cells resulted in the opposite trend. Furthermore, the PI3K/Akt pathway was involved in the effects of CNTN-1 on EMT progression in A549/DDP cells, verified by the xenograft mouse model. CNTN-1 promotes cisplatin resistance in human cisplatin-resistant lung adenocarcinoma through inducing the EMT process by activating the PI3K/Akt signaling pathway. CNTN-1 may be a potential therapeutic target to reverse chemoresistance in cisplatin-resistant lung adenocarcinoma.

Zhang R ，Sun S ，Ji F ，Liu C ，Lin H ，Xie L ，Yang H ，Tang W ，Zhou Y ，Xu J ，Li P ... -  《-》