LAPTM4B: A novel cancer-associated gene motivates multidrug resistance through efflux and activating PI3K/AKT signaling

Abstract

LAPTM4B (lysosomal protein transmembrane 4 beta) is a newly identified cancer-associated gene. Both of its mRNA and the encoded LAPTM4B-35 protein are significantly upregulated with more than 70% frequency in a wide variety of cancers. The LAPTM4B-35 level in cancer is evidenced to be an independent prognostic factor and its upregulation promotes cell proliferation, migration and invasion, as well as tumorigenesis in nude mice. In contrary, knockdown of LAPTM4B-35 expression by RNA interference (RNAi) reverses all of the above malignant phenotypes. We herein reveal a new role of LAPTM4B-35 in promoting multidrug resistance of cancer cells. Upregulation of LAPTM4B-35 motivates multidrug resistance by enhancement of efflux from cancer cells of a variety of chemodrugs with variant structures and properties, including doxorubicin, paclitaxel and cisplatin through colocalization and interaction of LAPTM4B-35 with multidrug resistance (MDR) 1 (P-glycoprotein, P-gp), and also by activation of PI3K/AKT signaling pathway through interaction of PPRP motif contained in the N-terminus of LAPTM4B-35 with the p85a regulatory subunit of PI3K. The specific inhibitors of PI3K and knockdown of LAPTM4B-35 expression by RNAi eliminate the multidrug resistance effect motivated by upregulation of LAPTM4B-35. In conclusion, LAPTM4B-35 motivates multidrug resistance of cancer cells by promoting drug efflux through colocalization and interaction with P-gp, and anti-apoptosis by activating PI3K/AKT signaling. These findings provide a promising novel strategy for sensitizing chemical therapy of cancers and increasing the chemotherapeutic efficacy through knockdown LAPTM4B-35 expression by RNAi.

The Transcription Factor AP4 Promotes Oncogenic Phenotypes and Cisplatin Resistance by Regulating LAPTM4B Expression

“…The inhibition of cell migration and invasion induced by AP4 shRNA was markedly rescued by LAPTM4B overexpression in both cell lines (Figure 4A, B). LAPTM4B has been shown to motivate multidrug resistance by activation the PI3K/AKT signaling pathway [30]. In our study, we detected the effects of PI3K specific inhibitor on AP4 and LAPTM4B associated MDR.…”

“…The PPRP motif in the N-terminus of LAPTM4B-35 protein directly binding to PI3K p85 α subunit could strongly phosphorylate AKT and then motivate MDR in Hela cells [30]. In the present study, we showed that silencing AP4 induced apoptosis and and protein levels were examined in MCF7 and MDA-MB-231 cells exposed to AP4 overexpression vector.…”

LAPTM4B polymorphism is associated with non-small cell lung cancer susceptibility and prognosis

“…It has been confirmed that LAPTM4B protein could upregulate some proliferation-promoting transcription factors such as c-Myc, c-Jun and c-Fos, and cell cycle-promoting proteins such as cyclin D1 and E (28). Meanwhile, it could also activate PI3K/AKT signaling pathway to motivate cellular multidrug resistance (31). A recent study clarified that cAMP responsive element binding protein-1 (CREB1) played an important role in LAPTM4B transcriptional regulation (32).…”

“…Furthermore, extensive studies have been performed to account for such outcomes. Studies have shown that upregulation of LAPTM4B could promote cell proliferation (28), invasion, migration (29) and may inhibit cell apoptosis (30,31) in vitro, while in nude mice the time of tumorigenesis was markedly shortened (29). It was assumed that various signal molecules were associated with cellular malignant transformation after the alteration of LAPTM4B protein expression level.…”

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

“…Upregulated LAPTM4B mRNA and protein levels have been documented in multiple cancers and cell lines, where they correlate with pathological grade and prognosis in vivo and promote proliferation, migration, invasion, and drug resistance in vitro. 35 In this study, LAPTM4B overexpression was identified in LUAD and LUSC tumor samples compared to normal tissues (Fig. 4), as well as in patients with poor OS in KIRC and LAML (Fig.…”