Silencing Glypican-1 enhances the antitumor effects of Pictilisib via downregulating PI3K/Akt/ERK signaling in chemo-resistant esophageal adenocarcinoma

Akshay Pratap; Andrea Qualman; Hedlund Garrett; Lindsey Westbrook; Erlinda The; Sanchayita Mitra; Mila Cordero; Kenneth Meza Monge; Juan-Pablo Idrovo; Argudit Chauhan; Linling Cheng; Mitchell Jay Cohen; Benedetto Mungo; Sachin Wani; Robert Alexander Meguid; Martin D McCarter; Xianzhong Meng

doi:10.1080/23723556.2023.2238873

Silencing Glypican-1 enhances the antitumor effects of Pictilisib via downregulating PI3K/Akt/ERK signaling in chemo-resistant esophageal adenocarcinoma

Mol Cell Oncol. 2023 Aug 15;10(1):2238873. doi: 10.1080/23723556.2023.2238873. eCollection 2023.

Authors

Akshay Pratap¹, Andrea Qualman¹, Hedlund Garrett², Lindsey Westbrook³, Erlinda The⁴, Sanchayita Mitra¹, Mila Cordero⁵, Kenneth Meza Monge¹, Juan-Pablo Idrovo¹, Argudit Chauhan⁶, Linling Cheng⁴, Mitchell Jay Cohen¹, Benedetto Mungo⁷, Sachin Wani⁸, Robert Alexander Meguid⁴, Martin D McCarter⁷, Xianzhong Meng⁴

Affiliations

¹ Division of Gastrointestinal Tumor and Endocrine Surgery, University of Colorado, Aurora, CO, USA.
² Department of Allergy and Clinical Immunology Flow Core, University of Colorado, Aurora, CO, USA.
³ Department of Pathology, University of Colorado, Aurora, CO, USA.
⁴ Division of Cardiothoracic Surgery, University of Colorado, Aurora, CO, USA.
⁵ School of Science, Engineering, & Technology, St. Mary's University, San Antonio, TX, USA.
⁶ Department of Biomedical Engineering, University of Colorado, Boulder, USA.
⁷ Division of Surgical Oncology, University of Colorado, Aurora, CO, USA.
⁸ Division of Gastroenterology and Hepatology, University of Colorado, Aurora, CO, USA.

Abstract

Poorly differentiated esophageal adenocarcinoma (PDEAC) has a dismal prognosis. Glypican-1(GPC-1) is known to be upregulated in several cancer types in contrast to healthy tissues, rendering it as a biomarker. Nevertheless, the potential therapeutic targeting of GPC-1 has not been explored in PDEAC. There is accumulating evidence that GPC-1, via upregulation of PI3K/Akt/ERK signaling, plays a crucial role in the progression and chemoresistance in cancer. Pictilisib, a class I pan PI3K inhibitor, has shown promising antitumor results in clinical trials, however, has not gained widespread success due to acquired drug resistance. This study investigated the role of GPC-1 in chemo-resistant PDEAC and appraises the impact of targeted silencing of GPC-1 on the antitumor effects of Pictilisib in PDEAC cell lines. Immunohistochemistry assays in PDEAC tissue specimens demonstrated a pronounced intensity of staining with GPC-1. Upregulation of GPC-1 was found to be correlated with advanced stage and poor prognosis. In-vitro studies examined the influence of GPC-1 knockdown and Pictilisib, both as individual agents and in combination, on cytotoxicity, cell cycle distribution, apoptosis, and gene expression profiles. Silencing GPC-1 alone showed significantly reduced cell viability, migration, colony formation, epithelial-mesenchymal transition, and stemness in PDEAC cells. Significantly, knockdown of GPC-1 combined with low-dose Pictilisib led to enhancement of cytotoxicity, cell cycle arrest, and apoptosis in ESO-26 and OE-33 cells. In the xenograft mouse model, the combination of Pictilisib and GPC-1 knockdown exhibited synergy. These findings suggest that GPC-1 represents a promising target to augment chemosensitivity in esophageal adenocarcinoma.

Keywords: Glypican-1; PI3K/Akt pathway; Poorly differentiated esophageal adenocarcinoma (PDEAC); chemoresistance; pictilisib.

Grants and funding

This work was supported by Intuitive Foundation Fellowship grant and ACS IRG #16-184-56 from the American Cancer Society to the University of Colorado Cancer Center.