Targeted knockdown of polo-like kinase 1 alters metabolic regulation in melanoma

Abstract

A limited number of studies have indicated an association of the mitotic kinase polo-like kinase 1 (PLK1) and cellular metabolism. Here, employing an inducible RNA interference approach in A375 melanoma cells coupled with a PCR array and multiple validation approaches, we demonstrated that PLK1 alters a number of genes associated with cellular metabolism. PLK1 knockdown resulted in a significant downregulation of IDH1, PDP2 and PCK1 and upregulation of FBP1. Ingenuity Pathway Analysis (IPA) identified that 1) glycolysis and the pentose phosphate pathway are major canonical pathways associated with PLK1, and 2) PLK1 inhibition-modulated genes were largely associated with cellular proliferation, with FBP1 being the key modulator. Further, BI 6727-mediated inhibition of PLK1 caused a decrease in PCK1 and increase in FBP1 in A375 melanoma cell implanted xenografts in vivo. Furthermore, an inverse correlation between PLK1 and FBP1 was found in melanoma cells, with FBP1 expression significantly downregulated in a panel of melanoma cells. In addition, BI 6727 treatment resulted in an upregulation in FBP1 in A375, Hs294T and G361 melanoma cells. Overall, our study suggest that PLK1 may be an important regulator of metabolism maintenance in melanoma cells.

Polo-like kinase 3 inhibits glucose metabolism in colorectal cancer by targeting HSP90/STAT3/HK2 signaling

“…PLKs are dysregulated in many types of cancer, such as liver cancer, brain cancer and ovarian cancer [9]. To date, only PLK1 was identified as an important coordinator of glucose metabolism in tumor cells [11, 12]. The roles of PLK2–5 in cancer glucose metabolism remain to be elucidated.…”

“…Li et al find that the phosphorylation of PTEN by PLK1 contributes to a tumor-promoting metabolic state [11]. In addition, targeting PLK1 significantly alters various genes associated with a decrease of cellular metabolism [12]. However, little is known about the overall pathophysiological contribution of PLK3 to CRC malignancy and glucose metabolism.…”

Polo-like kinase 1 coordinates biosynthesis during cell cycle progression by directly activating pentose phosphate pathway

“…Increasing evidence suggests that Plk1 is also involved in other cellular events in addition to mitosis. For instance, Plk1 functions to regulate DNA replication 17 , 18 and glycolysis indirectly through its target protein PTEN 19 or other metabolic pathways 20 . Recently, we have deciphered several metabolic inputs underlying the altered biosynthesis and cell cycle progression in cancer cells 21 – 23 .…”

Gluconeogenesis in cancer cells – Repurposing of a starvation-induced metabolic pathway?

“…Notably, PCK1 and G6PC were downregulated in liver and kidney cancer cells, but not in a panel of tumor cell lines from other tissues, by mTORC2, one of the complex forming members of mTOR [63]. Silencing of the mitotic kinase polo-like kinase 1 (PLK1) dramatically reduced levels of PCK1 mRNA and protein in melanoma cells, while FBP1 expression was increased, suggesting that the two enzymes are not regulated in the same direction in certain cancer cell types [100].…”