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Gene & Protein in Disease Verteporfin therapy for triple-negative breast cancer

study, no significant differences in the mRNA expression of the cellular apoptotic machinery. We have also encountered
either YAP or TAZ were observed with the VP treatment, elevated levels of cleaved caspase 3 and cleaved PARP upon
even under prolonged conditions. This finding may explain VP treatment. The data were consistent in YAP-silenced
that VP exerts no transcriptional changes on Hippo cells as well.
effectors but does tamper with the structural conformation There are previous reports of the antiproliferative and
of the protein. The significant reduction in CTGF, CYR61, anti-metastatic effects of VP on breast cancer cells [25,26] .
and MYC downstream target molecules of the YAP These studies, reported by the same group, have shown that
transduction again substantiates the hindered YAP/TAZ VP exerts anti-tumorigenic effects on different subtypes of
signaling.
breast cancer cells (luminal A, luminal B, and basal-like
We have also observed that, without any light cells) in a YAP-dependent manner. Overexpression of YAP
activation, VP inhibits TNBC cellular proliferation to a in TNBC cells is reported to correlate with proliferation
significant level in both dose- and time-dependent manner. and resistance to radiosensitivity and DNA damage .
[34]
Moreover, cells treated with VP exhibited an accumulated In our study, we found that, compared to non-TNBC,
cell number in the G0/G1 phase of the cell cycle with TNBC cells had higher YAP and TAZ expression as well
increasing concentration of the VP. Furthermore, a similar as higher downstream transactivity. In line with these
accumulation of the cells at the G0/G1 phase was observed data, we questioned the relevance of the upregulated YAP/
with YAP transiently silenced cells. The increased Cyclin TAZ activity in TNBC using pharmacological inhibition
D1 expression is the rate-limiting factor for the G1-S of the proteins. VP inhibited both YAP and TAZ protein
cellular progression, and its elevated expression is known expression in TNBC cells but did not affect the mRNA
to be sufficient for cell cycle completion . The cyclin- expressions. VP imparted an antiproliferative effect by
[29]
dependent kinase inhibitors p21 and p27 are well known to inducing cell cycle arrest at the G0/G1 phase and engaging
hinder Cyclin D1 activation . The decreased expression apoptotic machinery. Further transient silencing of YAP
[30]
of Cyclin D1 with elevated p21 and p27 corroborated alone was sufficient to recapitulate the same results in
the efficacy of VP to induce the G0/G1 phase cellular TNBC cells. The finding indicates that the anti-tumorigenic
arrest. Besides, MYC plays a central role in malignancy activity of VP is dependent on the YAP rather than the
by promoting cell proliferation, and decreased expression TAZ and points to the differential activity of the two Hippo
of the protein accumulates cells in the G1 phase of the effectors in TNBC cells.
cell cycle, eventually leading to cell death . MYC is
[31]
reported to be a major downstream target of YAP-TEAD 5. Conclusion
signaling . We show that with YAP inhibition, MYC We demonstrate that the predominance of nuclear YAP
[32]
expression is significantly downregulated in TNBC cells, accumulation in TNBC cells is coupled with a YAP-
which plausibly contributes to decreased cell proliferation dependent rewiring of cell proliferative signaling, ultimately
and cell cycle arrest. YAP-silenced cells also exhibited a contributing to cellular aggression. In conclusion, our
similar pattern of protein expression. The data perhaps study strongly supports the requisite of YAP signaling in
suggest that VP-induced cellular arrest is, in fact, due to modulating TNBC cellular proliferation and escaping
the depletion of the YAP transactivity in TNBC cells.
apoptotic mechanisms. We report the efficacy of VP
The components of the Hippo pathway were initially in attenuating proliferation in TNBC cells by inducing
discovered as regulators of organ size and development, cellular arrest and engaging apoptotic machinery.
and subsequently, the central role of the Hippo cascade in
restraining cell proliferation and promoting apoptosis in Acknowledgments
differentiating epithelia was established . In our study, we None.
[33]
observed decreased cellular viability upon VP treatment,
and in order to validate the type of cytotoxic effect exerted Funding
by VP, apoptosis assays by flow cytometric analysis were
performed. With increasing concentration of the VP, a This work was supported by funding from DBT-India (BT/
significant increase in cellular apoptosis was observed. One PR1/8812/COE/34/01/2017) and a fellowship grant from
of the key indicators of apoptosis is the activation of the ICMR (2020-7548/CMB-BMS).
cascade of caspase proteins, among which caspase 3 acts as Conflict of interest
the ultimate effector. PARP is crucial for genomic stability
in viable cells, and once the cells activate the apoptotic The authors declared no potential conflicts of interest with
machinery, the cleaved active form of caspase 3 executes respect to the research, authorship, and/or publication of
the cleavage of PARP protein and subsequently activates this article.

Volume 2 Issue 2 (2023) 9 https://doi.org/10.36922/gpd.0658