Chlorophyllides repress gain-of-function p53 mutated HNSCC cell proliferation via activation of p73 and repression of p53 aggregation in vitro and in vivo

被引：0

作者：

Cai, Bi-He ^{[1
]}

Wang, Yi-Ting ^{[2
]}

Chen, Chia-Chi ^{[1
,3
]}

Yeh, Fang-Yu ^{[1
]}

Lin, Yu-Rou ^{[1
]}

Lin, Ying-Chen ^{[4
]}

Wu, Tze-You ^{[5
]}

Wu, Kuan-Yo ^{[2
]}

Lien, Ching-Feng ^{[6
]}

Shih, Yu-Chen ^{[6
]}

Shaw, Jei-Fu ^{[2
]}

机构：

[1] I Shou Univ, Sch Med, Kaohsiung 82445, Taiwan

[2] I Shou Univ, Dept Med Sci & Biotechnol, Kaohsiung 82445, Taiwan

[3] E Da Hosp, Dept Pathol, Kaohsiung 82445, Taiwan

[4] I Shou Univ, Dept Med Lab Sci, Kaohsiung 82445, Taiwan

[5] I Shou Univ, Dept Biomed Engn, Kaohsiung 82445, Taiwan

[6] E DA Hosp, Dept Otolaryngol Head & Neck Surg, Kaohsiung 82445, Taiwan

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2025年 / 1871卷 / 03期

关键词：

p53; p73; Aggregation; Chlorophyllides; Gain of function mutation; HNSCC; WILD-TYPE P53; MUTANT P53; COLORECTAL-CANCER; RESTORES P53; MUTATIONS; AUTOPHAGY; PATHWAY; COAGGREGATION; GENE;

D O I：

10.1016/j.bbadis.2025.167662

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Head and neck squamous cell carcinoma (HNSCC) cells have a high p53 mutation rate, but there were rare reported about the p53 gain of function through the prion-like aggregated form in p53 mutated HNSCC cells. Thioflavin T (ThT) is used to stain prion-like proteins in cells. Previously, we found that ThT and p53 staining were co localized in HNSCC cells (Detroit 562 cells) with homozygous p53 R175H mutation. NAMPT inhibitor can repress ThT staining in Detroit 562 cells. In our previous study, co-treatment with p73 activator NSC59984 and NAMPT inhibitor FK886 synergistically repressed Detroit 562 cell proliferation. In this study, we found that two heterozygous p53-R280T mutation HNSCC cell lines, TW01 and HONE-1, also have the ThT staining signal. Treatment with chlorophyllides and p73 activator or NAMPT inhibitor did not synergistically repress cell proliferation in either Detroit 562 or HONE-1 cells. Chlorophyllides reduced the ThT aggregation signal in both Detroit 562 and HONE-1 cells. Chlorophyllides also induced p73 and caspase 3/7 expression and repressed NAMPT expression in both Detroit 562 and HONE-1 cells. Chlorophyllides reduced tumor size in vivo in Detroit 562 cells injected into a xenograft nude mice model, but this in vivo tumor repression effect was not found in p73 knockdown Detroit 562 cells. Moreover, NAMPT was repressed by chlorophyllides independent of p73 status in vivo. We thus concluded that chlorophyllides have a dual anticancer function when applied to HNSCC cells with p53 gain-of-function mutation, via activation of p73 and repression of p53 aggregation.

引用

页数：15

共 50 条

[41]

Kehrloesser S., Osterburg C., Tuppi M., Schafer B., Vousden K.H., Dotsch V., Intrinsic aggregation propensity of the p63 and p73 TI domains correlates with p53R175H interaction and suggests further significance of aggregation events in the p53 family, Cell Death Differ., 23, 12, pp. 1952-1960, (2016)

[42]

Cai B.H., Hsu Y.C., Yeh F.Y., Lin Y.R., Lu R.Y., Yu S.J., Shaw J.F., Wu M.H., Tsai Y.Z., Lin Y.C., Bai Z.Y., Shih Y.C., Liao R.Y., Kuo W.H., Hsu C.T., Lien C.F., Chen C.C., P63 and P73 activation in cancers with p53 mutation, Biomedicines, 10, 7, (2022)

[43]

Hong B., Prabhu V.V., Zhang S., van den Heuvel A.P., Dicker D.T., Kopelovich L., El-Deiry W.S., Prodigiosin rescues deficient p53 signaling and antitumor effects via upregulating p73 and disrupting its interaction with mutant p53, Cancer Res., 74, 4, pp. 1153-1165, (2014)

[44]

Prabhu V.V., Hong B., Allen J.E., Zhang S., Lulla A.R., Dicker D.T., El-Deiry W.S., Small-molecule prodigiosin restores p53 tumor suppressor activity in chemoresistant colorectal cancer stem cells via c-Jun-mediated ΔNp73 inhibition and p73 activation, Cancer Res., 76, 7, pp. 1989-1999, (2016)

[45]

Yi Y., Chen D., Ao J., Sun S., Wu M., Li X., Bergholz J., Zhang Y., Xiao Z.X., Metformin promotes AMP-activated protein kinase-independent suppression of ΔNp63α protein expression and inhibits cancer cell viability, J. Biol. Chem., 292, 13, pp. 5253-5261, (2017)

[46]

Yi Y., Zhang W., Yi J., Xiao Z.X., Role of p53 family proteins in metformin anticancer activities, J. Cancer, 10, 11, pp. 2434-2442, (2019)

[47]

Lunghi P., Costanzo A., Levrero M., Bonati A., Treatment with arsenic trioxide (ATO) and MEK1 inhibitor activates the p73-p53AIP1 apoptotic pathway in leukemia cells, Blood, 104, 2, pp. 519-525, (2004)

[48]

Rosenbluth J.M., Pietenpol J.A., mTOR regulates autophagy-associated genes downstream of p73, Autophagy, 5, 1, pp. 114-116, (2009)

[49]

Kenzelmann Broz D., Spano Mello S., Bieging K.T., Jiang D., Dusek R.L., Brady C.A., Sidow A., Attardi L.D., Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses, Genes Dev., 27, 9, pp. 1016-1031, (2013)

[50]

Shi K., An J., Shan L., Jiang Q., Li F., Ci Y., Wu P., Duan J., Hui K., Yang Y., Xu C., Survivin-2B promotes autophagy by accumulating IKK alpha in the nucleus of selenite-treated NB4 cells, Cell Death Dis., 5, 2, (2014)

← 1 2 3 4 5 →