PI3K/AKT/mTOR pathway and its related molecules participate in PROK1 silence-induced anti-tumor effects on pancreatic cancer

Feng Wang; Xiaogang Yan; Yongqiang Hua; Jianjun Song; Di Liu; Chun Yang; Fei Peng; Fuping Kang; Yongfeng Hui

doi:10.1515/biol-2022-0538

PI3K/AKT/mTOR pathway and its related molecules participate in PROK1 silence-induced anti-tumor effects on pancreatic cancer

Open Life Sci. 2023 Apr 10;18(1):20220538. doi: 10.1515/biol-2022-0538. eCollection 2023.

Authors

Feng Wang^{1

2}, Xiaogang Yan³, Yongqiang Hua^{4

5}, Jianjun Song^{1

2}, Di Liu^{1

2}, Chun Yang⁶, Fei Peng⁷, Fuping Kang^{1

2}, Yongfeng Hui^{1

2}

Affiliations

¹ Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, No. 804 South Shengli Street, Xingqing District, Yinchuan 750001, Ningxia, China.
² Ningxia Clinical Medical Research Center of Hepatobiliary and Pancreatic Surgical Diseases, Yinchuan 750001, China.
³ Department of Surgical Oncology, The First People's Hospital of Yinchuan, Yinchuan 750001, China.
⁴ Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
⁵ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
⁶ Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan 750001, China.
⁷ Department of Hepatobiliary Pancreatic Surgery, Edong Healthcare Huangshi Central Hospital, Huangshi 435002, Hubei, China.

Abstract

The PI3K/AKT/mTOR (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin) pathway can be initiated by PROK1 (prokineticin 1), but its effect and mechanism of action in pancreatic carcinoma (PC) are not fully understood. In this study, we elucidated the roles of PROK1 and its related molecules in PC in vivo. PANC-1 cells with PROK1 knockdown were injected into BALB/c nude mice. The growth and weight of the tumor were monitored and measured, which was followed by TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling), immunohistochemical staining, and hematoxylin and eosin staining. The key proteins related to proliferation, apoptosis, and the PI3K/AKT/mTOR pathway were determined by Western blotting. We also used public databases to identify the molecules related to PROK1. The reduction of PROK1 inhibited angiopoiesis and promoted apoptosis in vivo. PCNA-1, cyclin D1, and Bcl-2 decreased considerably, while Bax and cleaved caspase-3 increased significantly after PROK1 inhibition. The PI3K/AKT/mTOR signal inhibition was also closely associated with PROK1 knockdown. The possible related molecules of PROK1, such as von Willebrand factor, were screened and considered to be involved in the aberrant activation of PI3K/AKT. In conclusion, PROK1 knockdown significantly prevented tumor growth and promoted apoptosis of human PC cells in vivo, where the PI3K/AKT/mTOR pathway was probably inhibited. Therefore, PROK1, along with its related molecules, might be important targets for PC therapy.

Keywords: PI3K/AKT/mTOR; PROK1; apoptosis; pancreatic cancer; proliferation.