Suppressed PLIN3 frequently occurs in prostate cancer, promoting docetaxel resistance via intensified autophagy, an event reversed by chloroquine

Abstract

Lipid metabolism reprogramming is one of the adaptive events that drive tumor development and survival, and may account for resistance to chemotherapeutic drugs. Perilipins are structural proteins associated with lipophagy and lipid droplet integrity, and their overexpression is associated with tumor aggressiveness. Here, we sought to explore the role of lipid droplet-related protein perilipin-3 (PLIN3) in prostate cancer (PCa) chemotherapy. We investigated the role of PLIN3 suppression in docetaxel cytotoxic activity in PCa cell lines. Additional effects of PLIN3 depletion on autophagy-related proteins and gene expression patterns, apoptotic potential, proliferation rate, and ATP levels were examined. Depletion of PLIN3 resulted in docetaxel resistance, accompanied by enhanced autophagic flux. We further assessed the synergistic effect of autophagy suppression with chloroquine on docetaxel cytotoxicity. Inhibition of autophagy with chloroquine reversed chemoresistance of stably transfected shPLIN3 PCa cell lines, with no effect on the parental ones. The shPLIN3 cell lines also exhibited reduced Caspase-9 related apoptosis initiation. Moreover, we assessed PLIN3 expression in a series of PCa tissue specimens, were complete or partial loss of PLIN3 expression was frequently noted in 70% of the evaluated specimens. Following PLIN3 silencing, PCa cells were characterized by impaired lipophagy and acquired an enhanced autophagic response upon docetaxel-induced cytotoxic stress. Such an adaptation leads to resistance to docetaxel, which could be reversed by the autophagy blocker chloroquine. Given the frequent loss of PLIN3 expression in PCa specimens, we suggest that combination of docetaxel with chloroquine may improve the efficacy of docetaxel treatment in PLIN3-deficient cancer patients. Supplementary Information The online version contains supplementary material available at 10.1007/s12032-021-01566-y.

Lipid droplets-related Perilipin-3: potential immune checkpoint and oncogene in oral squamous cell carcinoma

“…PLIN3, as a surface protein of LDs, can regulate LD biosynthesis and degradation [ 42 ]; PLIN3 associates with LDs in a manner that is responsive to the status of neutral lipid synthesis and storage in the cell [ 21 ]. At the same time, PLIN3 plays an important role in cell viability and autophagy, which can lead to drug resistance to treatment [ 43 ]. Kaplan–Meier curves revealed that elevated PLIN3 predicted poor DFS and OS in clear cell renal cell carcinoma [ 22 ].…”

“…Kaplan–Meier curves revealed that elevated PLIN3 predicted poor DFS and OS in clear cell renal cell carcinoma [ 22 ]. In prostate cancer, PLIN3 overexpression promotes tumor progression [ 43 ]. Similar to previous studies, we demonstrated that PLIN3 was upregulated and predicted a poor prognosis in OSCC, suggesting that PLIN3 accumulated in cells to serve as a conservative oncogene to promote cancer development.…”

Epidemiological, Clinical, and Genomic Profile in Head and Neck Cancer Patients and Their Families

“…Patient 229 presented a heterozygous loss of the TICAM1 (TIR domain-containing adaptor molecule 1) and PLIN3 (lipid droplet-related protein perilipin-3) genes. Perilipins are structural proteins associated with lipophagy and lipid droplet integrity, and their overexpression is associated with tumor aggressiveness, while TICAM1 participates in immune and inflammation responses to malignant cells [ 51 , 52 ].…”

A comprehensive gene expression profile analysis of prostate cancer cells resistant to paclitaxel and the potent target to reverse resistance

“…Lipid metabolism was an important driving force for tumor occurrence and development, and it was also the reason why PCa was resistant to chemotherapy drugs. 26 It showed that AEGs were involved in lipid metabolism to achieve the regulation of resistance to PCa.…”