TY - JOUR
T1 - Exploiting arginine auxotrophy with pegylated arginine deiminase (ADI-PEG20) to sensitize pancreatic cancer to radiotherapy via metabolic dysregulation
AU - Singh, Pankaj K.
AU - Deorukhkar, Amit A.
AU - Venkatesulu, Bhanu P.
AU - Li, Xiaolin
AU - Tailor, Ramesh
AU - Bomalaski, John S.
AU - Krishnan, Sunil
N1 - Funding Information:
We thank Christine P. Wogan, MS, for help with reading and editing the manuscript. We also thank Mr. Keith L. Sanders for statistical analysis and creating heatmap. We also acknowledge support from the MD Anderson Cancer Center Support Grant CA92261 and the John E. and Dorothy J. Harris Professorship (to S. Krishnan). This work was supported in part by research grant 00002962 from Polaris Pharmaceuticals, Inc. (to P.K. Singh) and in part by Cancer Center Support (Core) Grant (P30 CA16672) from the US NCI, NIH to The University of Texas MD Anderson Cancer and the John E. and Dorothy J. Harris Endowed Professorship (to S. Krishnan).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - Distinct metabolic vulnerabilities of cancer cells compared with normal cells can potentially be exploited for therapeutic targeting. Deficiency of argininosuccinate synthetase-1 (ASS1) in pancreatic cancers creates auxotrophy for the semiessential amino acid arginine. We explored the therapeutic potential of depleting exogenous arginine via pegylated arginine deiminase (ADI-PEG20) treatment as an adjunct to radiotherapy. We evaluated the efficacy of treatment of human pancreatic cancer cell lines and xenografts with ADI-PEG20 and radiation via clonogenic assays and tumor growth delay experiments. We also investigated potential mechanisms of action using reverse-phase protein array, Western blotting, and IHC and immunofluorescence staining. ADI-PEG20 potently radiosen-sitized ASS1-deficient pancreatic cancer cells (MiaPaCa-2, Panc-1, AsPc-1, HPAC, and CaPan-1), but not ASS1-expressing cell lines (Bxpc3, L3.6pl, and SW1990). Reverse phase protein array studies confirmed increased expression of proteins related to endoplasmic reticulum (ER) stress and apoptosis, which were confirmed by Western blot analysis. Inhibition of ER stress signaling with 4-phenylbutyrate abrogated the expression of ER stress proteins and reversed radiosensitization by ADI-PEG20. Independent in vivo studies in two xenograft models confirmed significant tumor growth delays, which were associated with enhanced expression of ER stress proteins and apoptosis markers and reduced expression of proliferation and angiogenesis markers. ADI-PEG20 augmented the effects of radiation by triggering the ER stress pathway, leading to apoptosis in pancreatic tumor cells.
AB - Distinct metabolic vulnerabilities of cancer cells compared with normal cells can potentially be exploited for therapeutic targeting. Deficiency of argininosuccinate synthetase-1 (ASS1) in pancreatic cancers creates auxotrophy for the semiessential amino acid arginine. We explored the therapeutic potential of depleting exogenous arginine via pegylated arginine deiminase (ADI-PEG20) treatment as an adjunct to radiotherapy. We evaluated the efficacy of treatment of human pancreatic cancer cell lines and xenografts with ADI-PEG20 and radiation via clonogenic assays and tumor growth delay experiments. We also investigated potential mechanisms of action using reverse-phase protein array, Western blotting, and IHC and immunofluorescence staining. ADI-PEG20 potently radiosen-sitized ASS1-deficient pancreatic cancer cells (MiaPaCa-2, Panc-1, AsPc-1, HPAC, and CaPan-1), but not ASS1-expressing cell lines (Bxpc3, L3.6pl, and SW1990). Reverse phase protein array studies confirmed increased expression of proteins related to endoplasmic reticulum (ER) stress and apoptosis, which were confirmed by Western blot analysis. Inhibition of ER stress signaling with 4-phenylbutyrate abrogated the expression of ER stress proteins and reversed radiosensitization by ADI-PEG20. Independent in vivo studies in two xenograft models confirmed significant tumor growth delays, which were associated with enhanced expression of ER stress proteins and apoptosis markers and reduced expression of proliferation and angiogenesis markers. ADI-PEG20 augmented the effects of radiation by triggering the ER stress pathway, leading to apoptosis in pancreatic tumor cells.
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U2 - 10.1158/1535-7163.MCT-18-0708
DO - 10.1158/1535-7163.MCT-18-0708
M3 - Article
C2 - 31395686
AN - SCOPUS:85076064370
SN - 1535-7163
VL - 18
SP - 2381
EP - 2393
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 12
ER -