Methionine aminopeptidase 2 as a potential target in pancreatic ductal adenocarcinoma

Eliana Steinberg; Rawnaq Esa; Ouri Schwob; Tal Stern; Natalie Orehov; Gideon Zamir; Ayala Hubert; Dipak Panigrahy; Ofra Benny

Methionine aminopeptidase 2 as a potential target in pancreatic ductal adenocarcinoma

Am J Transl Res. 2022 Sep 15;14(9):6243-6255. eCollection 2022.

Authors

Eliana Steinberg¹, Rawnaq Esa¹, Ouri Schwob¹, Tal Stern¹, Natalie Orehov¹, Gideon Zamir², Ayala Hubert³, Dipak Panigrahy^{4

5}, Ofra Benny¹

Affiliations

¹ The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem Israel.
² Department of Surgery, Hadassah-Hebrew University Medical School Ein Kerem, Jerusalem 91120, Israel.
³ Sharett Institute of Oncology, Hadassah-Hebrew University Medical School Ein Kerem, Jerusalem 91120, Israel.
⁴ Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA 02215, USA.
⁵ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA 02215, USA.

PMID: 36247237
PMCID: PMC9556484

Abstract

Pancreatic ductal adenocarcinoma (PDA) is an aggressive metastatic cancer with a very low survival rate. This tumor is hypovascularized and characterized by severe hypoxic regions, yet these regions are not impeded by the oxidative stress in their microenvironment. PDA's high resilience raises the need to find new effective therapeutic targets. This study investigated the suitability of methionine aminopeptidase 2 (MetAp2), a metallopeptidase known to play an important role in tumor progression, as a new target for treating PDA. In our examination of patient-derived PDA tissues, we found that MetAp2 is highly expressed in metastatic regions compared with primary sites. At the cellular level, we found that the basal expression levels of MetAp2 in pancreatic cancer cells were higher than its levels in endothelial cells. Pancreatic cancer cells showed a significant suppression of proliferation in a dose-dependent manner upon exposure to TNP-470, a selective MetAp2 inhibitor. In addition, a significant reduction in glutathione (GSH) levels - known for its importance in alleviating oxidative stress - was detected in all treated cells, suggesting a possible anti-cancer activity mechanism that would be feasible for treating highly hypoxic PDA tumors. Furthermore, in an orthotopic pancreatic cancer murine model, systemic oral treatment with a MetAp2 inhibitor significantly reduced tumors' growth. Taken together, our findings indicate that MetAp2 enhances tumor sensitivity to hypoxia and may provide an effective target for treating hypoxic tumors with high expression levels of MetAp2.

Keywords: GSH; MetAp2; PDA; hypoxia; metastasis.