Novel pactamycin analogs induce p53 dependent cell-cycle arrest at S-phase in human head and neck squamous cell carcinoma (HNSCC) cells

Gunjan Guha, Wanli Lu, Shan Li, Xiaobo Liang, Molly Kulesz-Martin, Taifo Mahmud, Arup Kumar Indra, Gitali Ganguli-Indra

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

(AKI) Pactamycin, although putatively touted as a potent antitumor agent, has never been used as an anticancer drug due to its high cytotoxicity. In this study, we characterized the effects of two novel biosynthetically engineered analogs of pactamycin, de-6MSA-7-demethyl-7-deoxypactamycin (TM-025) and 7-demethyl-7-deoxypactamycin (TM-026), in head and neck squamous cell carcinoma (HNSCC) cell lines SCC25 and SCC104. Both TM-025 and TM-026 exert growth inhibitory effects on HNSCC cells by inhibiting cell proliferation. Interestingly, unlike their parent compound pactamycin, the analogs do not inhibit synthesis of nascent protein in a cell-based assay. Furthermore, they do not induce apoptosis or autophagy in a dose- or a time-dependent manner, but induce mild senescence in the tested cell lines. Cell cycle analysis demonstrated that both analogs significantly induce cell cycle arrest of the HNSCC cells at S-phase resulting in reduced accumulation of G2/M-phase cells. The pactamycin analogs induce expression of cell cycle regulatory proteins including master regulator p53, its downstream target p21Cip1/WAF1, p27kip21, p19, cyclin E, total and phospho Cdc2 (Tyr15) and Cdc25C. Besides, the analogs mildly reduce cyclin D1 expression without affecting expression of cyclin B, Cdk2 and Cdk4. Specific inhibition of p53 by pifithrin- α reduces the percentage of cells accumulated in S-phase, suggesting contribution of p53 to S-phase increase. Altogether, our results demonstrate that Pactamycin analogs TM-025 and TM-026 induce senescence and inhibit proliferation of HNSCC cells via accumulation in S-phase through possible contribution of p53. The two PCT analogs can be widely used as research tools for cell cycle inhibition studies in proliferating cancer cells with specific mechanisms of action.

Original languageEnglish (US)
Article numbere0125322
JournalPLoS One
Volume10
Issue number5
DOIs
StatePublished - May 4 2015

Fingerprint

Pactamycin
squamous cell carcinoma
Cell Cycle Checkpoints
S Phase
interphase
neck
Cells
cyclins
cell cycle
antineoplastic agents
cells
cell lines
Cell Cycle
Cyclin B
Cyclin E
Cell Cycle Proteins
cyclin-dependent kinase
autophagy
Cyclin D1
regulatory proteins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Novel pactamycin analogs induce p53 dependent cell-cycle arrest at S-phase in human head and neck squamous cell carcinoma (HNSCC) cells. / Guha, Gunjan; Lu, Wanli; Li, Shan; Liang, Xiaobo; Kulesz-Martin, Molly; Mahmud, Taifo; Indra, Arup Kumar; Ganguli-Indra, Gitali.

In: PLoS One, Vol. 10, No. 5, e0125322, 04.05.2015.

Research output: Contribution to journalArticle

Guha, Gunjan ; Lu, Wanli ; Li, Shan ; Liang, Xiaobo ; Kulesz-Martin, Molly ; Mahmud, Taifo ; Indra, Arup Kumar ; Ganguli-Indra, Gitali. / Novel pactamycin analogs induce p53 dependent cell-cycle arrest at S-phase in human head and neck squamous cell carcinoma (HNSCC) cells. In: PLoS One. 2015 ; Vol. 10, No. 5.
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AU - Liang, Xiaobo

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AU - Mahmud, Taifo

AU - Indra, Arup Kumar

AU - Ganguli-Indra, Gitali

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