Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

ABSTRACT

Colorectal cancer (CRC) is one of the most common malignancies worldwide and remains a major clinical challenge. Periplocin, a major bioactive component of the traditional Chinese herb Cortex periplocae, has recently been reported to be a potential anticancer drug. However, the mechanism of action is poorly understood. Here, we show that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo. Mechanistically, periplocin promotes lysosomal damage and induces apoptosis in CRC cells. Notably, periplocin upregulates LGALS3 (galectin 3) by binding and preventing LGALS3 from Lys210 ubiquitination-mediated proteasomal degradation, leading to the induction of excessive lysophagy and resultant exacerbation of lysosomal damage. Inhibition of LGALS3-mediated lysophagy attenuates periplocin-induced lysosomal damage and growth inhibition in CRC cells, suggesting a critical role of lysophagy in the anticancer effects of periplocin. Taken together, our results reveal a novel link between periplocin and the lysophagy machinery, and indicate periplocin as a potential therapeutic option for the treatment of CRC.

Abbreviations: 3-MA: 3-methyladenine; ACACA/ACC1: acetyl-CoA carboxylase alpha; AMPK: adenosine monophosphate-activated protein kinase; AO: Acridine orange; ATG5: autophagy related 5; ATG7: autophagy related 7; CALM: calmodulin; CHX: cycloheximide; CRC: colorectal cancer; CQ: chloroquine; CTSB: cathepsin B; CTSD: cathepsin D; ESCRT: endosomal sorting complex required for transport; LAMP1: lysosomal associated membrane protein 1; LMP: lysosomal membrane permeabilization; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MKI67/Ki-67: marker of proliferation Ki-67; MTOR: mechanistic target of rapamycin kinase; P2RX4/P2X4: purinergic receptor P2X 4; PARP1/PARP: poly(ADP-ribose) polymerase 1; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TRIM16: tripartite motif containing 16.

KEYWORDS:

• Autophagic flux
• colorectal cancer
• LGALS3 (galectin 3)
• lysophagy
• lysosomal damage
• periplocin

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2023.2239042

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (81821002, 82130082, 82341004, 82273122, 82073081, 82172588, 82002963), National Key Research and Development Project of China (2020YFA0509400), Guangdong Basic and Applied Basic Research Foundation (2019B030302012), the Science and Technology Department of Sichuan Province (2017SZ0057), the Chengdu Science and Technology Program (2019-YF05-00715-SN), and 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD22007).