PKM2 Is Overexpressed in Glioma Tissues, and Its Inhibition Highly Increases Late Apoptosis in U87MG Cells With Low-density Specificity

PARK, JAE HYEON; LEE, JIN-SOL; Oh, Yunmoon; LEE, JI SUN; PARK, HAE EUN; Lee, Haeun; PARK, YEON SU; Kyung, So Young; Kim, Hyung Sik; Yoon, Sungpil

doi:10.21873/invivo.12755

Cited by 8 publications

(18 citation statements)

References 33 publications

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“…Detailed information on the tissue microarray samples is presented in Table I. Immunohistochemical analysis was performed to investigate PKM2 expression in adjacent normal and breast tumor tissue samples as previously described (18,19). The tissue microarray slides were treated with xylene and ethanol, followed by boiling in sodium citrate buffer for 20 min.…”

Section: Breast Tissue Microarray and Immunohistochemistry (Ihc)mentioning

confidence: 99%

“…For assessing immunoreactivity and histological appearance, all tissue microarray slides were examined and scored. The intensity of PKM2 immunostaining in individual cells (average of duplicates) was scored according to the following scale as previously described (18,19): 0, no staining; 1, weak intensity; 2, moderate intensity; and 3, strong intensity. The percentage of cells with positive PKM2 immunostaining at each intensity level was estimated (0 to 100%).…”

Section: Breast Tissue Microarray and Immunohistochemistry (Ihc)mentioning

confidence: 99%

“…Microscopic observations were performed as previously described (18,(30)(31)(32)(33), in order to examine the effect of gliotoxin, shikonin, compound 3K, or VIC on cellular growth. Briefly, MDA-MB-231 or KB cells were grown at low density (1.5×10 5 cells), and were treated with 5 nM VIC, 1-1.5 μM gliotoxin, 1-1.5 μM shikonin, or 10 μM compound 3K for 1 day.…”

Section: Microscopic Observationmentioning

confidence: 99%

“…Fluorescence-activated cell sorting (FACS) analysis. FACS analysis was performed as previously described (18,(30)(31)(32)(33). Briefly, MDA-MB-231 cells were grown in 60 mm diameter dishes with high density (4×10 5 cells), and were treated with 5 nM VIC, 1-1.5 μM gliotoxin, 1-1.5 μM shikonin, 10 μM compound, 1-1.5 μM gliotoxin with 1-1.5 μM shikonin, 5 nM VIC with 1-1.5 μM shikonin, 5 nM VIC with 1-1.5 μM gliotoxin, 5 nM VIC with 10 μM compound 3K, 10 μM compound 3K with 1-1.5 μM gliotoxin, 10 μM compound 3K with 1-1.5 μM shikonin, or 0.1% DMSO for 24 h. The detached by trypsin were washed, and suspended in 75% ethanol for 24 h at -20˚C.…”

Section: In Vivomentioning

confidence: 99%

“…In this study, we identified a correlation between TNBC and PKM2 overexpression. Furthermore, we assessed the anticancer effects of PKM2 inhibitors (shikonin and compound 3K) on human MDA-MB-231 cells (18)(19)(20)(21). In particular, we tested a newly identified PKM2 inhibitor gliotoxin (isolated from marine environments), which directly bound to PKM2 and inhibited its glycolytic activity in a U87MG glioma study (22).…”

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Combination Treatment Using Pyruvate Kinase M2 Inhibitors for the Sensitization of High Density Triple-negative Breast Cancer Cells

LEE

et al. 2022

In Vivo

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Background/Aim: Few studies have examined the correlation between pyruvate kinase M2 (PKM2) overexpression and triple-negative breast cancer (TNBC). TNBC is considered incurable with the currently available treatments, highlighting the need for alternative therapeutic targets. Materials and Methods: PKM2 expression was examined immunohistochemically in human breast tumor samples. Furthermore, we studied the effect of three PKM2 inhibitors (gliotoxin, shikonin, and compound 3K) in the MDA-MB-231 TNBC cell line. Results: PKM2 overexpression correlates with TNBC. Interestingly, most TNBC tissues showed increased levels of PKM2 compared to those of receptor-positive breast cancer tissues. This suggests that PKM2 overexpression is an important factor in the development of TNBC. MDA-MB-231 TNBC cells are resistant to anticancer drugs, such as vincristine (VIC) compared to other cancer cells. We found that the recently developed PKM2 inhibitor gliotoxin sensitized MDA-MB-231 cells at a relatively low dose to the same extent as the known PKM2 inhibitor shikonin, suggesting that PKM2 inhibitors could be an effective treatment for TNBC. Detailed sensitization mechanisms were also analyzed. Both gliotoxin and shikonin highly increased late apoptosis in MDA-MB-231 cells, as revealed by annexin V staining. However, MDA-MB-231 cells with high cellular density inhibited the sensitizing effect of PKM2 inhibitors; therefore, we investigated ways to overcome this inhibitory effect. We found that gliotoxin+shikonin co-treatment highly increased toxicity in MDA-MB-231 cells with high density, whereas either VIC+gliotoxin or VIC+shikonin were not effective. Thus, combination therapy with various PKM2 inhibitors may be more effective than combination therapy with anticancer drugs. Gliotoxin+shikonin co-treatment did not increase S or G 2 arrest in cells, suggesting that the co-treatment showed a high increase in apoptosis without S or G 2 arrest. We confirmed that another recently developed PKM2 inhibitor compound 3K had similar mechanisms of sensitizing MDA-MB-231 cells, suggesting that PKM2 inhibitors have similar sensitization mechanisms in TNBC. Conclusion: PKM2 is a regulator of the oncogenic function of TNBC, and combination therapy with various PKM2 inhibitors may be effective for high-density TNBC. Targeting PKM2 in TNBC lays the foundation for the development of PKM2 inhibitors as promising anti-TNBC agents.Among the different molecular subtypes of breast cancer, triple-negative breast cancer (TNBC) is an extremely aggressive subtype; it is associated with poor prognosis and high mortality rates, despite systemic therapy (1, 2). TNBC is also a heterogeneous disease compared to the luminal and HER2-enriched subtypes (1-3). Chemotherapy and combination chemotherapy are the conventional treatments for TNBC; however, resistant types of TNBC are prevalent (3-6). Although several clinical trials targeting molecules specific to TNBC, including poly (ADP-ribose) polymerase (PARP), epidermal growth factor receptor (EGFR), protein kin...

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Section: Breast Tissue Microarray and Immunohistochemistry (Ihc)mentioning

confidence: 99%

Section: Breast Tissue Microarray and Immunohistochemistry (Ihc)mentioning

confidence: 99%

Section: Microscopic Observationmentioning

confidence: 99%

Section: In Vivomentioning

confidence: 99%

mentioning

confidence: 99%

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Combination Treatment Using Pyruvate Kinase M2 Inhibitors for the Sensitization of High Density Triple-negative Breast Cancer Cells

LEE

et al. 2022

In Vivo

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N6‐isopentenyladenosine inhibits aerobic glycolysis in glioblastoma cells by targeting PKM2 expression and activity

Pagano,

Coppola,

Navarra

et al. 2024

FEBS Open Bio

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Glioblastoma (GBM) is a primary tumor in the central nervous system with poor prognosis. It exhibits elevated glucose uptake and lactate production. This metabolic state of aerobic glycolysis is known as the Warburg effect. N6‐isopentenyladenosine (iPA), a natural cytokine modified with an isopentenyl moiety derived from the mevalonate pathway, has well‐established anti‐tumor activity. It inhibits cell proliferation in glioma cells, inducing cell death by apoptosis and/or necroptosis. In the present study, we found that iPA inhibits aerobic glycolysis in unmodified U87MG cells and in the same cell line engineered to over‐express wild‐type epidermal growth factor receptor (EGFR) or EGFR variant III (vIII), as well as in a primary GBM4 patient‐derived cell line. The detection of glycolysis showed that iPA treatment suppressed ATP and lactate production. We also evaluated the response of iPA treatment in normal human astrocyte primary cells, healthy counterpart cells of the brain. Aerobic glycolysis in treated normal human astrocyte cells did not show significant changes compared to GBM cells. To determine the mechanism of iPA action on aerobic glycolysis, we investigated the expression of certain enzymes involved in this metabolic pathway. We observed that iPA reduced the expression of pyruvate kinase M2 (PKM2), which plays a key role in the regulation of aerobic glycolysis, promoting tumor cell proliferation. The reduction of PKM2 expression is a result of the inhibition of the inhibitor of nuclear factor kappa‐B kinase subunit, beta/nuclear factor‐kappa B pathway upon iPA treatment. In conclusion, these experimental results show that iPA may inhibit aerobic glycolysis of GBM in stabilized cell lines and primary GBM cells by targeting the expression and activity of PKM2.

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Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy

Cheng,

Shi,

et al. 2023

Advanced Science

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Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast proliferation even under oxygen‐sufficient conditions. This metabolic alteration not only favors tumor cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition to serving as a byproduct of glycolytic tumor cells, lactate also plays a central role in the construction of acidic and immunosuppressive tumor microenvironment, resulting in therapeutic tolerance. Recently, targeted drug delivery and inherent therapeutic properties of nanomaterials have attracted great attention, and research on modulating lactate metabolism based on nanomaterials to enhance antitumor therapy has exploded. In this review, the advanced tumor therapy strategies based on nanomaterials that interfere with lactate metabolism are discussed, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting the “lactate shuttle”. Furthermore, recent advances in combining lactate metabolism modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy, and reactive oxygen species‐related therapies, etc., which have achieved cooperatively enhanced therapeutic outcomes, are summarized. Finally, foreseeable challenges and prospective developments are also reviewed for the future development of this field.

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PKM2 Is Overexpressed in Glioma Tissues, and Its Inhibition Highly Increases Late Apoptosis in U87MG Cells With Low-density Specificity

Cited by 8 publications

References 33 publications

Combination Treatment Using Pyruvate Kinase M2 Inhibitors for the Sensitization of High Density Triple-negative Breast Cancer Cells

Combination Treatment Using Pyruvate Kinase M2 Inhibitors for the Sensitization of High Density Triple-negative Breast Cancer Cells

N6‐isopentenyladenosine inhibits aerobic glycolysis in glioblastoma cells by targeting PKM2 expression and activity

Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy

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