RLIP76 regulates PI3K/Akt signaling and chemo-radiotherapy resistance in pancreatic cancer.
Pancreatic cancer is an aggressive malignancy with characteristic metastatic course of disease and resistance to conventional chemo-radiotherapy. RLIP76 is a multi-functional cell membrane protein that functions as a major mercapturic acid pathway transporter as well as key regulator of receptor-lig...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3317991?pdf=render |
| _version_ | 1818941333538078720 |
|---|---|
| author | Kathryn Leake Jyotsana Singhal Lokesh Dalasanur Nagaprashantha Sanjay Awasthi Sharad S Singhal |
| author_facet | Kathryn Leake Jyotsana Singhal Lokesh Dalasanur Nagaprashantha Sanjay Awasthi Sharad S Singhal |
| author_sort | Kathryn Leake |
| collection | DOAJ |
| description | Pancreatic cancer is an aggressive malignancy with characteristic metastatic course of disease and resistance to conventional chemo-radiotherapy. RLIP76 is a multi-functional cell membrane protein that functions as a major mercapturic acid pathway transporter as well as key regulator of receptor-ligand complexes. In this regard, we investigated the significance of targeting RLIP76 on PI3K/Akt pathway and mechanisms regulating response to chemo-radiotherapy.Cell survival was assessed by MTT and colony forming assays. Cellular levels of proteins and phosphorylation was determined by Western blot analyses. The impact on apoptosis was determined by TUNEL assay. The anti-cancer effects of RLIP76 targeted interventions in vivo were determined using mice xenograft model of the pancreatic cancer. The regulation of doxorubicin transport and radiation sensitivity were determined by transport studies and colony forming assays, respectively.Our current studies reveal an encompassing model for the role of RLIP76 in regulating the levels of fundamental proteins like PI3K, Akt, E-cadherin, CDK4, Bcl2 and PCNA which are of specific importance in the signal transduction from critical upstream signaling cascades that determine the proliferation, apoptosis and differentiation of pancreatic cancer cells. RLIP76 depletion also caused marked and sustained regression of established human BxPC-3 pancreatic cancer tumors in nude mouse xenograft model. RLIP76 turned out to be a major regulator of drug transport along with contributing to the radiation resistance in pancreatic cancer.RLIP76 represents a mechanistically significant target for developing effective interventions in aggressive and refractory pancreatic cancers. |
| first_indexed | 2024-12-20T06:53:52Z |
| format | Article |
| id | doaj.art-b4a68b05462342d299f9d248ede6779a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T06:53:52Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b4a68b05462342d299f9d248ede6779a2022-12-21T19:49:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0174e3458210.1371/journal.pone.0034582RLIP76 regulates PI3K/Akt signaling and chemo-radiotherapy resistance in pancreatic cancer.Kathryn LeakeJyotsana SinghalLokesh Dalasanur NagaprashanthaSanjay AwasthiSharad S SinghalPancreatic cancer is an aggressive malignancy with characteristic metastatic course of disease and resistance to conventional chemo-radiotherapy. RLIP76 is a multi-functional cell membrane protein that functions as a major mercapturic acid pathway transporter as well as key regulator of receptor-ligand complexes. In this regard, we investigated the significance of targeting RLIP76 on PI3K/Akt pathway and mechanisms regulating response to chemo-radiotherapy.Cell survival was assessed by MTT and colony forming assays. Cellular levels of proteins and phosphorylation was determined by Western blot analyses. The impact on apoptosis was determined by TUNEL assay. The anti-cancer effects of RLIP76 targeted interventions in vivo were determined using mice xenograft model of the pancreatic cancer. The regulation of doxorubicin transport and radiation sensitivity were determined by transport studies and colony forming assays, respectively.Our current studies reveal an encompassing model for the role of RLIP76 in regulating the levels of fundamental proteins like PI3K, Akt, E-cadherin, CDK4, Bcl2 and PCNA which are of specific importance in the signal transduction from critical upstream signaling cascades that determine the proliferation, apoptosis and differentiation of pancreatic cancer cells. RLIP76 depletion also caused marked and sustained regression of established human BxPC-3 pancreatic cancer tumors in nude mouse xenograft model. RLIP76 turned out to be a major regulator of drug transport along with contributing to the radiation resistance in pancreatic cancer.RLIP76 represents a mechanistically significant target for developing effective interventions in aggressive and refractory pancreatic cancers.http://europepmc.org/articles/PMC3317991?pdf=render |
| spellingShingle | Kathryn Leake Jyotsana Singhal Lokesh Dalasanur Nagaprashantha Sanjay Awasthi Sharad S Singhal RLIP76 regulates PI3K/Akt signaling and chemo-radiotherapy resistance in pancreatic cancer. PLoS ONE |
| title | RLIP76 regulates PI3K/Akt signaling and chemo-radiotherapy resistance in pancreatic cancer. |
| title_full | RLIP76 regulates PI3K/Akt signaling and chemo-radiotherapy resistance in pancreatic cancer. |
| title_fullStr | RLIP76 regulates PI3K/Akt signaling and chemo-radiotherapy resistance in pancreatic cancer. |
| title_full_unstemmed | RLIP76 regulates PI3K/Akt signaling and chemo-radiotherapy resistance in pancreatic cancer. |
| title_short | RLIP76 regulates PI3K/Akt signaling and chemo-radiotherapy resistance in pancreatic cancer. |
| title_sort | rlip76 regulates pi3k akt signaling and chemo radiotherapy resistance in pancreatic cancer |
| url | http://europepmc.org/articles/PMC3317991?pdf=render |
| work_keys_str_mv | AT kathrynleake rlip76regulatespi3kaktsignalingandchemoradiotherapyresistanceinpancreaticcancer AT jyotsanasinghal rlip76regulatespi3kaktsignalingandchemoradiotherapyresistanceinpancreaticcancer AT lokeshdalasanurnagaprashantha rlip76regulatespi3kaktsignalingandchemoradiotherapyresistanceinpancreaticcancer AT sanjayawasthi rlip76regulatespi3kaktsignalingandchemoradiotherapyresistanceinpancreaticcancer AT sharadssinghal rlip76regulatespi3kaktsignalingandchemoradiotherapyresistanceinpancreaticcancer |