PP-1α and PP-1γ Display Antagonism and Differential Roles in Tumorigenicity of Lung Cancer Cells

Abstract

Protein serine/threonine phosphatases are important cellular signaling molecules and play major roles in regulating many different functions including cell proliferation, senescence, programmed cell death, and oncogenic cell transformation. Among different serine/threonine phosphatases, PP-1 and PP-2A contribute to more than 90% phosphatase activities in eukaryotes. While the functions of PP-2A in cell transformation and tumorigenesis have been well established, the role of PP-1 in carcinogenesis remains to be further explored. Moreover, PP-1 exists in different isoforms, whether these isoforms have differential functions in tumorigenesis remains to be examined. In the present study, we demonstrated that in lung cancer 1299 cells, PP1α and PP- 1 & γ exist in an antagonizing balance. In the parent H1299 cells, PP-1γ is dominant, about 4-fold higher than that of PP-1α. Overexpression of PP-1α significantly down-regulates PP-1γ at both mRNA and protein levels. In contrast, knockdown of PP-1α leads to upregulation of PP-1γ. Moreover, overexpression of PP-1α significantly attenuates the ability of the H1299 cells in promoting tumorigenicity as tested in immuno-deficient nude mice. This attenuation is derived from the halted cell cycle progression, which is largely attributed by the changed RB-E2F activity. Together, our results demonstrate that PP-1α and PP-1γ not only antagonize each other in lung cancer cells, but also display differential functions in tumorigenicity.

Differential contribution of protein phosphatase 1α to cell transformation of different cell types

“…Collectively, the data supported the oncogenic role of PP1α in lung cancer formation, which is in line with previous studies highlighting that downregulation or inactivation of PP1α is associated with poor prognosis (24) and radioresistance (25) of lung cancer cells. However, negative correlation of PP1α with lung cancer has also been reported (23).…”

“…contribution of PP1α to lung cancer remains ambiguous. For example, PP1α was revealed to be involved in the RIF1-induced tumor growth of the lung cancer cell line H1299 (22), while overexpression of PP1α in H1299 cells restricted tumor formation in vivo (23). Furthermore, downregulation or inactivation of PP1α was revealed to be associated with poor prognosis (24) and radioresistance (25) of lung cancer cells.…”

Strategies for Targeting Serine/Threonine Protein Phosphatases with Small Molecules in Cancer

“…At the early stage, PPPases were simply identified as tumor suppressor proteins or oncogenic proteins. In recent years, accumulating evidence has indicated that PPPases play different roles in distinct cancers, which may be due to the diversity of regulatory subunits of PPPases. − Here, we list a few examples, mainly involving PP1, PP2A, and PP4 to illustrate that PPPases could act as both tumor promoters and tumor suppressors in specific cancers (Figure B).…”

“…PP1Cα knockdown induced cell rounding and increased proliferation inhibition; PP1Cβ knockdown led to cell flattening and enlargement, with enrichment of lamellipodia; and PP1Cγ1 knockdown changed the distribution of cell cycle phases. PP1Cα and PP1Cγ1 play antagonizing roles and display different functions in lung cancer cells . For more details about the underlying mechanism, see the review by Felgueiras et al PP2A is another well-studied PPPase subfamily that was previously generally defined as a tumor suppressor. − Its two completely different roles in cancer were uncovered by later studies.…”

“…PP1Cα and PP1Cγ1 play antagonizing roles and display different functions in lung cancer cells. 75 For more details about the underlying mechanism, see the review by Felgueiras et al 76 PP2A is another well-studied PPPase subfamily that was previously generally defined as a tumor suppressor. 77−80 Its two completely different roles in cancer were uncovered by later studies.…”