Page 211 - 2025中醫藥與天然藥物聯合學術研討會-中醫藥與天然藥物的挑戰Ｘ機遇與未來大會手冊

PP-29

The anticancer activity of andrographolide against pancreatic ductal

adenocarcinoma by targeting Hsp90/p53/mevalonate pathway axis

2
1
1
Yun-Rui Li, Chiao-Ju Liao, Kai-Ru Zhuang, Y u -Chia Wang, Lee-Chiang Lo, Shu-
3
1
Ling Fu*
,1

1 Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
2 Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei,
Taiwan
3 Department of Chemistry, National Taiwan University, Taipei, Taiwan
* Email: slfu@nycu.edu.tw

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, due
to limited therapeutic strategies and lack of early diagnostic biomarkers. Mutations in TP53
occur in 50–70% of PDAC cases. Missense mutations are most prevalent and result in single
amino-acid alterations within the DNA-binding domain, generating oncogenic gain-of-function
(GOF) proteins such as p53 R273H and p53 R248W . We recently found that knockout of p53 R273H in
PANC-1 cells reduces malignancy, highlighting oncogenic p53 as a potential therapeutic target.
The mevalonate (MVA) pathway provides essential metabolites for cellular responses and is
activated by oncogenic p53. Aberrant upregulation of the MVA pathway correlates with PDAC
progression. Thus, agents targeting p53/MVA pathway are potential anti-PDAC therapeutics.
Andrographolide (Andro), the major bioactive component of Andrographis paniculata,
possesses anticancer and anti-inflammatory activities. Our previous studies showed Andro
suppresses PDAC malignancy and delays tumor growth in vivo. In this study, we found Andro
inhibited oncogenic p53 protein in PDAC cells without affecting transcription. Knockdown of
Hsp90α, a chaperone essential for p53 stability, also reduced oncogenic p53 protein. Using a
fluorophore derivative, Andro-NBD, we confirmed direct binding of Andro to Hsp90α through
Michael addition. Thus, Andro destabilizes oncogenic p53 in an Hsp90-dependent manner.
Furthermore, Andro downregulated MVA pathway enzymes, and this decrease was also
observed in p53 R273H -knockout cells. Andro reduced membrane localization of KRAS,
indicating that MVA-downstream KRAS prenylation was impaired. Notably, supplementation
with farnesyl pyrophosphate (FPP) partially restored proliferation suppressed by Andro. In
conclusion, Andro suppresses the Hsp90/oncogenic p53/MVA axis, underscoring its therapeutic
potential in PDAC.

Keywords: PDAC; Oncogenic p53; Mevalonate pathway; Andrographis paniculate;
Andrographolide; Hsp90-α