Inhibition of secretory leukocyte protease inhibitor (SLPI) promotes the PUMA-mediated apoptosis and chemosensitivity to cisplatin in colorectal cancer cells

Zhijiang Wei; Guiying Liu; Rufu Jia; Wei Zhang; Li Li; Yuanyuan Zhang; Zhijing Wang; Xiyong Bai

doi:10.1007/s12672-022-00535-9

Inhibition of secretory leukocyte protease inhibitor (SLPI) promotes the PUMA-mediated apoptosis and chemosensitivity to cisplatin in colorectal cancer cells

Discov Oncol. 2023 Jan 3;14(1):1. doi: 10.1007/s12672-022-00535-9.

Authors

Zhijiang Wei¹, Guiying Liu², Rufu Jia³, Wei Zhang², Li Li³, Yuanyuan Zhang², Zhijing Wang³, Xiyong Bai²

Affiliations

¹ The First Department of Tumor Surgery, Cangzhou Central Hospital, Cangzhou, 061001, Hebei, People's Republic of China. weizj780@126.com.
² The First Department of Tumor Surgery, Cangzhou Central Hospital, Cangzhou, 061001, Hebei, People's Republic of China.
³ The Brain Science Hospital of CangZhou Central Hospital, Cangzhou, 061001, Hebei, People's Republic of China.

Abstract

Background: Aberrant expression of Secretory Leukocyte Protease Inhibitor (SLPI) has been associated with human cancer growth and its suppression was identified as a potential target for anti-cancer drugs, particularly in colorectal cancer. However, the underlying mechanism by which SLPI affected the development of drug resistance in CRC remains unclear.

Objective: This study investigated the role of SLPI in the p53-up-regulated modulator of apoptosis (PUMA)-mediated CRC cells' apoptosis and their chemosensitivity to Cisplatin.

Methods: A series of qRT-PCR and western blot analyses were performed to characterize the expressions of SLPI, PUMA, and Akt in CRC lines. Tunel, transwell, and CCK-8 analyses were monitored to define the impacts of the siRNA-mediated knockdown of SLPI on CRC cell development. Furthermore, in vivo development of CRC was evaluated in nude mice infected with siSLPI or Cisplatin alone or both, and Ki67 and caspase-3 immunohistochemistry assay was monitored on multiple tissue microarray from the same cohort.

Results: Our results showed that SLPI inhibition strongly promoted the expressions of the pro-apoptotic protein PUMA, cleaved-caspase3 and Bax and reduced the cell viability of HT29 and HT116 cell lines in vitro. In addition, siSLPI knockdown effectively suppressed both Akt and FoxO3 proteins and improved the sensitivity to cisplatin chemotherapy. Xenograft tumor assay revealed a lowered growth in mice treated with Cisplatin, while combined treatment of siSLPI achieved more significant anticancer effects than Cisplatin alone.

Conclusions: Taken together, these findings demonstrated that suppression of SLPI might repress the growth of human colorectal cancer cells both in vitro and in vivo. These results suggested SLPI as a novel resistance factor to Cisplatin, and a combination of Cisplatin and SLPI inhibitor be beneficial for colorectal cancer therapy.

Keywords: Chemosensitivity; Cisplatin; Colorectal cancer; NF-κB signaling; PUMA; Secretory leukocyte protease inhibitor.