Deacetylation of LAMP1 drives lipophagy‐dependent generation of free fatty acids by Abrus agglutinin to promote senescence in prostate cancer

Abstract

Therapy-induced senescence in cancer cells is an irreversible antiproliferative state, which inhibits tumor growth and is therefore a potent anti-neoplastic mechanism. In this study, low doses of Abrus agglutinin (AGG)-induced senescence through autophagy in prostate carcinoma cells (PC3) and inhibited proliferation. The inhibition of autophagy with 3methyl adenine reversed AGG-induced senescence, thus confirming that AGG-triggered senescence required autophagy. AGG treatment also led to lipophagy-mediated accumulation of free fatty acids (FFAs), with a concomitant decrease in the number of lipid droplets. Lalistat, a lysosomal acid lipase inhibitor, abrogated AGG-induced lipophagy and senescence in PC3 cells, indicating that lipophagy is essential for AGG-induced senescence. The accumulation of FFAs increased reactive oxygen species generation, a known facilitator of senescence, which was also reduced in the presence of lalistat. Furthermore, AGG upregulated silent mating type information regulator 2 homolog 1 (SIRT1), while the presence of sirtinol reduced autophagy flux and the senescent phenotype in the AGG-treated cells. Mechanistically, AGG-induced cytoplasmic SIRT1 deacetylated a Lys residue on the cytoplasmic domain of lysosome-associated membrane protein 1 (LAMP1), an autolysosomal protein, resulting in lipophagy and senescence. Taken together, our findings demonstrate a novel SIRT1/LAMP1/lipophagy axis mediating AGGinduced senescence in prostate cancer cells. K E Y W O R D SAbrus agglutinin, free fatty acid, LAMP1, lipophagy, reactive oxygen species, senescence, SIRT1

The diversity and breadth of cancer cell fatty acid metabolism

“…Some of the molecular mechanisms that facilitate lipophagy have been identified, and recent examples include RAB7 and ATG5 [146,147], PNPLA5 [148], ATG14 and Ulk1 [149], MAP1S [150], and LAMP1 [151]. In general, lipophagy plays a tumor suppressor role as it leads to increased intracellular free fatty acid levels, which promotes cell death via ferroptosis, ROS production, and ER stress [149,151]. However, it has also been proposed that autophagy can play a pro-tumor role in nutrient-deprived situations where mobilization of fatty acids via this pathway is used for subsequent catabolic and anabolic processing [145].…”

Lipid Droplets in Cancer

“…Adipocyte-derived FAs were found to stimulate AMPKdependent lipophagy and mitochondrial energy production, which were required for the survival of neighboring cancer cells during starvation. On the contrary, in prostate cancer cells, the activation of lipophagy may occur in response to SIRT1mediated acetylation of LAMP1 and lead to proliferative senescence, likely as a consequence of elevated oxidative stress (Panda et al 2019). Accordingly, excessive lipophagy leads to an overflow of free FAs causing mitochondrial damage, ER stress, and cancer cell death in cervical cancer cells (Mukhopadhyay et al 2017).…”

The expression and clinical significance of murine double minute 2, lysosome-associated membrane protein 1, and P-glycoprotein in pediatric acute lymphoblastic leukemia

“…ALL is a malignant tumor caused by the abnormal proliferation of lymphocyte-derived B-line or T-line cells in the bone marrow. Abnormally proliferated primitive cells can inhibit normal hematopoietic function, even spreading to the meninges, lymphatic system, gonads, and liver (16,17). In recent years, various protein molecules have attracted widespread attention for their roles in tumor cell invasion and metastasis.…”

“…MDM2 overexpression can produce the effect of inactivating point mutations of the P53 gene, and through the formation of P53-P90 gene points, it affects the activation of P53 transcription. Moreover, when MDM2 is highly expressed, it can directly bind to the target DNA, produce an anti-P53 effect and antagonize the effect of P53, promoting tumor invasion and development (16,21).…”