Plac8 Links Oncogenic Mutations to Regulation of Autophagy and Is Critical to Pancreatic Cancer Progression

Abstract

Summary Mutations in p53 and RAS potently cooperate in oncogenic transformation and correspondingly these genetic alterations frequently coexist in pancreatic ductal adenocarcinoma (PDA) and other human cancers. Previously we identified a set of genes synergistically activated by combined RAS and p53 mutations as frequent downstream mediators of tumorigenesis. Here, we show that the synergistically activated gene Plac8 is critical for pancreatic cancer growth. Silencing of Plac8 in cell lines suppresses tumor formation by blocking autophagy, a process essential for maintaining metabolic homeostasis in PDA, and genetic inactivation in an engineered mouse model inhibits PDA progression. We show that Plac8 is a critical regulator of the autophagic machinery, localizing to the lysosomal compartment and facilitating lysosome-autophagosome fusion. Plac8 thus provides a mechanistic link between primary oncogenic mutations and the induction of autophagy, a central mechanism of metabolic reprogramming, during PDA progression.

Addiction to Coupling of the Warburg Effect with Glutamine Catabolism in Cancer Cells

“…Oncogenic p53 and Ras mutations cooperate to induce many transformation-specific phenotypes (Kinsey et al, 2014; McMurray et al, 2008; Smith and Land, 2012; Xia and Land, 2007), and, accordingly, many of the metabolic phenotypes observed here were cooperatively induced (Figure 1K). However, a number of these metabolic activities were induced predominately by expression of either mp53 or oncogenic Ras.…”

“…It remains unclear, however, at what point of the multi-step process of carcinogenesis the glycolytic phenotype emerges and whether this transition is driven by cell-intrinsic mechanisms or by selective forces in the cancer microenvironment (e.g., oxygen limitation). We have extensively used young adult murine colon (YAMC) cells (Whitehead et al, 1993) transduced with activated Ras and mutant p53 to investigate the molecular mechanisms underlying the cooperative nature of malignant cell transformation, which has revealed cancer cell-specific vulnerabilities relevant to human disease (Kinsey et al, 2014; McMurray et al, 2008; Smith and Land, 2012; Xia and Land, 2007; Experimental Procedures). This model is therefore well suited to investigate the metabolic changes associated with the transition to malignancy.…”

“…Mechanistic insights into the complex structure of cellular regulation underlying malignant cell transformation come from exploration into how distinct oncogenic mutations cooperate to induce such a profound transition (Kinsey et al, 2014; Lloyd et al, 1997; McMurray et al, 2008; Sewing et al, 1997; Smith and Land, 2012; Xia and Land, 2007). In this context, it is notable that numerous genes essential to tumorigenesis can readily be identified by virtue of their synergistic response to cooperating oncogenic mutations.…”

NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis

“…The top identified genes were then further selected for their relevance to cancer and are depicted in Supplementary Table 1. Among the genes downregulated after NFAT1 silencing were follistatin (FST), which has been reported as a contributor to bone metastasis (16), and placenta-specific 8 (PLAC8), whose overexpression has been reported to protect cancer cells from apoptosis (17-19). Downregulation was also observed in the frizzeld family receptor 4 (FZD4) and the nicotinamide N-methyltransferase (NNMT) genes.…”

PLAC8 Localizes to the Inner Plasma Membrane of Pancreatic Cancer Cells and Regulates Cell Growth and Disease Progression through Critical Cell-Cycle Regulatory Pathways

“…A recent report by Kinsey and colleagues (36) suggested that PLAC8 expression promotes tumor progression in epithelial tumors (including pancreatic cancer) via autophagy-related mechanisms. Our own results, however, clearly exclude autophagy-related functions of PLAC8 in pancreatic cancer cells.…”