Kinase PIM1 promotes prostate cancer cell growth via c-Myc-RPS7-driven ribosomal stress

Abstract

Ribosomal stress is known to increase cancer risk, however, the molecular mechanism underlying its various effects on cancer remains unclear. To decipher this puzzle, we investigated the upstream signaling pathway that might be involved in promoting ribosomal stress that leads to tumor progression. Our results suggested that inhibition of kinase PIM1 attenuated PC3 cell growth and motility following the condensed cellular body and decreased protein translation in PIM1-inhibited cells. In addition, PIM1 was found to be a component of the small 40S ribosomal subunit, and could regulate the expression of RPS7. Our investigation also revealed that PIM1 enhanced the protein stability of c-Myc. Furthermore, a functional E-box motif was found upstream of the transcription start site in RPS7, and RPS7 has been proven to be a transcriptional target of c-Myc. Additionally, knocking down RPS7 dramatically reduced cell growth in vitro and in vivo, while enhancing RPS7 expression reversed the condensed cellular body and decreased protein translation resulted from PIM1 inhibition. Finally, BCR-free survival and overall survival analysis indicated that the concomitant upregulation of PIM1 and RPS7 correlated with the worst prognosis of prostate cancer (PCa). Overall, our results demonstrated that kinase PIM1 promotes cell growth through c-Myc-RPS7 induced ribosomal stress in PCa. These findings substantially expanded our understanding on the molecular mechanism of PIM1 promoted abnormal ribosomal biosynthesis in tumorigenesis and tumor progression in PCa, Therapies that target molecules involved in PIM1-RPS7 induced ribosomal stress could provide a promising approach to treating PCa.

PIM-1 Is Overexpressed at a High Frequency in Circulating Tumor Cells from Metastatic Castration-Resistant Prostate Cancer Patients

“…Recent data have shown that PIM activation is induced by tumor microenvironment changes, such as hypoxia, and causes resistance to angiogenesis inhibitors [21]. PIM-1 is a component of the small 40S ribosomal subunit and could regulate the expression of ribosomal small subunit protein-7, RPS7, demonstrating that ribosome-targeting drugs may be effective against diverse CRPC subtypes including AR-null disease [22,23]. Moreover, PIM-1 is thought to promote the carcinogenesis by cooperating with myc as transgenic mouse study has demonstrated that PIM1 enhanced c-Myc-induced tumorigenesis in PCa [24].…”

GATA1 regulates the microRNA‑328‑3p/PIM1 axis via circular RNA ITGB1 to promote renal ischemia/reperfusion injury in HK‑2 cells

“…PIM1 belongs to the Ser/Thr protein kinase family and functions as a proto-oncogene in human malignancies ( 36 ). PIM1 plays a role in the regulation of cell proliferation and survival in breast cancer ( 37 ), prostate cancer ( 38 ) and colorectal cancer ( 39 ). A role in hypoxia environment has been described for PIM1, since the apoptosis of rat cardiomyocytes was inhibited by PIM1 overexpression to enhance autophagy in spite of oxidative stress ( 40 ).…”

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

“…Studies indicate that the serine/threonine protein kinase pim 1 is known to be an oncogene and is present in the cytoplasm and nucleus and is capable of phosphorylating different targets, most of which are involved in the cell cycle and apoptosis processes . Pim1 is overexpressed in various tumours such as breast cancer and prostate cancer and promotes tumour progression by promoting cell proliferation, survival and inhibition of apoptosis . Moreover, Pim1 promotes cancer cells growth by enhancing the Warburg effect and promotes epithelial‐mesenchymal transition and oncogenesis .…”